The role of melatonin as an antioxidant in the follicle
© Tamura et al; licensee BioMed Central Ltd. 2012
Received: 29 November 2011
Accepted: 26 January 2012
Published: 26 January 2012
Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an anti-oxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.
Reactive oxygen species (ROS) are formed continuously in cells as a consequence of both oxidative biochemical reactions and external factors. While physiological levels of oxygen are necessary for cells to live, ROS such as superoxide radical (O2-), hydroxyl radical (·OH), and hydrogen peroxide (H2O2) are generated from oxygen. ROS can regulate cell function by controlling the production and activation of substances that have biological activities and by activating key downstream cell-signaling pathways [1–3]. However, surplus generation of ROS interact with lipid, protein and nucleic acid, resulting in a loss of membrane integrity, structural or functional changes in proteins, and damage in nucleic acids. Therefore, an increase in the production of ROS have detrimental effects on cell function and contributes significantly to several diseases, including those that may compromise reproduction and fertility .
ROS are produced within the follicle, especially during the ovulatory process. ROS play a physiological role in the process of ovulation, e.g. follicle rupture. However, an excessive amount of ROS cause oxidative stress and may damage oocyte and granulosa cells. Accumulating data have shown that ROS accelarate oocyte aging and deteriorate oocyte quality [5, 6]. On the other hand, antioxidant defense systems, such as superoxide dismutase (SOD) or glutathione (GSH), are present in follicles. The balance between ROS and antioxidants within the follicle seems to be critical to the function of oocyte and granulosa cells.
Melatonin, a hormone mainly synthesized in the pineal gland, has multiple effects on a number of different physiological processes. Melatonin plays a key role in a variety of important physiological functions, including circadian rhythms , reproductive , neuroendocrine , cardiovascular , neuroimmunological , oncostatic actions . We already reported that melatonin plays a role in lipid metabolism , pregnancy and parturition time [14–16], and corpus luteum (CL) function . Some effects of melatonin are mediated through specific membrane receptors, but many of them seem to rely on its potential as a direct free radical scavenger, a process that requires no receptor. A growing number of studies have demonstrated that melatonin is a powerful direct scavenger of free radicals. In contrast to the majority of other known radical scavengers, melatonin is multifunctional and a universal antioxidant. The high lipophilicity and hydrophilicity of melatonin permits its rapid transfer into other organs and fluids, and melatonin can easily pass through cell membranes. Interestingly, high levels of melatonin have been found in human follicular fluid [18, 19]. We already reported that human preovulatory follicular fluids contain higher concentrations of melatonin than of plasma and the melatonin concentrations in follicular fluids increased depending on follicular growth . Although the physiological roles of melatonin in follicular fluid have not been understood, it is possible that melatonin is the most effective antioxidant in the follicle. The purpose of this current review is to summarize recent developments in the field of melatonin research, with a focus on how melatonin directly protects oocyte from oxidative stress within the ovarian follicle.
Ovulation and reactive oxygen species (ROS)
ROS is locally produced during follicular rupture and may be involved in the ovulation process. Luteinizing hormone (LH) surge induces a dissolution of the basement membrane between the granulosa and theca interna layers and an expansion of the theca capillaries into the avascular granulosa cell layer to form a dense network of capillaries. Macrophages and neutrophiles are well-documented to reside in follicles; it is also well-documented that they are taken into the follicles [21, 22]. Tremendous amounts of free radicals are produced within the follicle not only by macrophages and neutrophiles but also by the endothelial cells of the capillaries. Locally produced ROS seems to have an essential role on follicle rupture, and ROS also have an important role as second messengers modulating the expression of genes that govern physiological processes of oocyte maturation [23, 24]. However, excess ROS can also be responsible for oxidative stress; they can damage molecules and structures of oocyte and granulosa cells within the follicle. ROS must be continuously deactivated to keep only the small amount necessary to maintain normal cell function. Follicular components, cumulus cells and the follicular fluid, may protect the oocytes from the damaging effects of ROS [25–27]. It is well recognized that endogenous antioxidant enzymes and non-enzymatic antioxidants are present in the follicles and are working to combat or reduce ROS. Failure or deficiency of these oocyte defenses could result in accumulation of ROS and the development of oxidative stress with resultant oocyte damage . Additionally, ROS may be overproduced in response to several conditions, such as infections, inflammation, chemotherapy, radiation, and superovulation as an infertility therapy.
It is well documented that antioxidant enzymes, such as (SOD), glutathione peroxidase (GPx) and catalase, and non-enzymatic antioxidants, such as vitamin E, vitamin C, glutathione, uric acid and albumin, are present in the follicles [4, 5, 32]. Reduced antioxidant enzyme levels, such as GPx, are reported in the follicular fluids of women with unexplained infertility . Another report demonstrated that a higher level of SOD activity in follicular fluid efficiently reduced DNA damage caused by oxidative stress in porcine oocytes and cumulus cells, resulting in successful fertilization and development to the blastocyst stage after in vitro insemination; however, these abilities were interrupted by the SOD inhibitor . When mice were given antioxidant supplements (vitamins C and E), an increased number of normal MII oocytes and decreased percentage of apoptotic oocytes were observed in comparison with the control group . The balance between ROS and antioxidants within the follicle seems to be critical for oocytes.
Melatonin as a free radical scavenger
Although melatonin exerts effects through its receptors, melatonin also can act as a powerful direct free radical scavenger. In 1993, melatonin was discovered to function as a direct free radical scavenger when it was shown to detoxify the highly reactive hydroxyl radical (·OH) [35, 36]. Since then, many reports have confirmed the ability of melatonin to reduce oxidative stress [37, 38]. In these investigations, melatonin was found to scavenge both oxygen- and nitrogen-based reactants [39, 40] in several subcellular organelles . Melatonin works in a variety of ways to reduce the levels of oxidative stress. It has been shown that melatonin has the capability of quenching reactive oxygen as well as reactive nitrogen species including superoxide radical (O2-), hydroxyl radical (·OH), singlet oxygen (1O2), hydrogen peroxide (H2O2), hypochlorous acid (HOCl), nitric oxide (NO·) and the peroxynitrite anion (ONOO-) [41–44]. Three key players are involved in ROS damage to cells: hydrogen peroxide (H2O2), superoxide radical (O2-), and hydroxyl radical (·OH). H2O2 and superoxide radicals (O2-) are thought to create less damage than hydroxyl radical (·OH), however, in the presence of free iron, specifically ferrous iron, H2O2 is converted to hydroxyl radical (Fenton reaction). Hydroxyl radical (·OH) is the most potent free radicals and is known to produce damage to all biological membranes and DNA. Melatonin can easily pass through cell membranes because of its properties of lipophilicity and hydrophilicity, and it has been demonstrated that a high levels of melatonin exist not only in cytoplasm but also beside the nucleus. The antioxidant properties of melatonin as a cell protector have been extensively studied and a previous report demonstrated that the melatonin's ability to detoxify the hydroxyl radical (·OH) was higher than well-known scavengers including vitamin C and vitamin E .
Not only is melatonin itself a direct free radical scavenger, but also metabolites that are formed during these interactions, i.e., cyclic 3-hydroxmelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), are likewise excellent scavengers of reactive species [40, 41, 45–47]. In addition, melatonin has a high capability to detoxify ROS and suppresses the oxidative effect indirectly by enhancing the production of endogenous antioxidants. Melatonin has been stimulates activities and mRNA levels of antioxidative enzymes including (SOD), (GPx), and catalase [48, 49]. Thereby, these multiple actions of melatonin protect cells from ROS-mediated lipid peroxidation, protein destruction and nuclear DNA damage [50–54].
Melatonin and reproduction
The roles of melatonin in reproduction are focused on its direct actions in the ovary. Melatonin can pass through all cell membranes and enter all tissues because of its lipophilic property, however, it specifically concentrates in the ovary when injected systemically . High levels of melatonin are found in human preovulatory follicular fluid at concentrations which are higher than serum levels [18, 19]. We previously demonstrated that melatonin concentrations in the ovary showed a similar phasic variation with high levels during mid-dark and low levels during mid-light, just as in the pineal gland and serum of hamsters . These concentrations were highest in proestrus, when the ovary has preovulatory follicles, during the estrus cycle. We also found the concentrations of preovulatory follicular fluid (> 18 mm) in in-vitro fertilization and embryo transfer (IVF-ET) patients are significantly higher than in small (10-12 mm) and middle follicles (15-16 mm) . These results demonstrated that melatonin levels in ovarian follicles increase depending on follicular growth. We presume that the majority of melatonin found in follicular fluid enters the follicle from blood because no clear mRNA expression of NAT (the rate-limiting enzyme of melatonin) could be found in the granulosa cells of rats and humans (unpublished data), and administration of melatonin dose dependently increased melatonin concentrations in the follicle in human (data not shown). Increased melatonin in follicular fluid seems to have an important role in ovulation.
Melatonin, oocyte quality, and embryo development
High quality oocytes produce well-developed embryos. After fertilization, ooplasm becomes the embryo cytoplasm, but the spermatozoon's participation in this process is minimal. It has been thought that the first steps of embryogenesis are controlled exclusively by maternal information present in the oocyte. For this reason, the quality of oocytes is a key factor in determining the quality of the early steps of embryo development. Oocyte maturation begins with the resumption of meiosis, and oocytes are arrested at prophase of the first meiotic division. Only fully grown oocytes can resume meiosis in response to LH surge. Oocytes pass through the first meiotic division and then become arrested at metaphase of the second meiotic division until fertilization. During this long period of meiotic maturation, oocyte accumulate molecules of mRNA, proteins, lipid and sugars as well as oxidative stress.
Clinical trial of melatonin for infertility patients
As summarized above, a growing amount of literature has demonstrated that melatonin and/or melatonin treatment may have a beneficial effect on oocyte maturation and embryo development. Poor oocyte quality is one of the most intractable causes of infertility in women. Melatonin treatment can be a useful infertility treatment and, therefore recently has been applied to infertility patients for the first time.
To document an association between melatonin and ovarian oxidative stress, human follicular fluids were sampled during oocyte retrieval for the purpose of IVF-ET and concentrations of melatonin and 8-OHdG were measured. The study revealed an inverse correlation between intra-follicular concentrations melatonin and 8-OHdG, suggesting that melatonin in the follicle diffuses into the cumulus and oocytes to protect them from free radical damage. When patients were given a 3 mg tablet of melatonin orally at 22:00 hr from the fifth day of the previous menstrual cycle until the day of oocyte retrieval, intra-follicular concentrations of melatonin rose from 112 pg/ml in the control cycle (without melatonin treatment) to 432 pg/ml after daily melatonin treatment. Intra-follicular concentrations of 8-OHdG and HEL, a damaged lipid product, were decreased after melatonin treatment compared to those in the prior cycle. The result demonstrates that melatonin treatment reduces intra-follicular oxidative damage. To investigate the clinical usefulness of melatonin administration, the effect of melatonin treatment on clinical outcome of IVF-ET was examined for 115 patients who failed to become pregnant in the previous IVF-ET cycle with a low fertilization rate (< 50%). In 56 patients with melatonin treatment, the fertilization rate (50.0 ± 38.0%) was markedly improved compared with the previous IVF-ET cycle (20.2 ± 19.0%), and 11 of 56 patients (19.6%) achieved pregnancy. On the other hand, in 59 patients who were not given melatonin, the fertilization rate (22.8 ± 19.0% vs 20.9 ± 16.5%) was not significantly changed, and only 6 of 59 patients (10.2%) achieved pregnancy. These results show that melatonin administration increases intra-follicular melatonin concentrations, reduces intra-follicular oxidative damage and elevates fertilization and pregnancy rates.
To our knowledge, our study represents the first clinical usefulness of melatonin treatment for infertility patients. Melatonin is likely to become a treatment for improving oocyte quality for women who cannot become pregnant because of poor oocyte quality.
This work was supported in part by Grants-in-Aid 20591918, 21592099, and 21791559 for Scientific Research from the Ministry of Education, Science, and Culture, Japan.
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