|Year : 2019 | Volume
| Issue : 3 | Page : 170-176
Role of oxidative stress and antioxidant therapies in endometriosis
Kalianee Devi Baboo, Zheng-Yun Chen, Xin-Mei Zhang
Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China
|Date of Submission||19-Feb-2019|
|Date of Web Publication||27-Sep-2019|
Department of Gynecology, Women's Hospital, Zhejiang University School of Medicine, No. 1 Xueshi Road, Hangzhou 310006
Source of Support: None, Conflict of Interest: None
Endometriosis (EMS) is a common gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. It is commonly associated with pelvic pain and infertility. The exact pathogenesis remains unclear and many hypotheses have been suggested. In recent years, accumulating evidence indicates that oxidative stress (OS) plays a role in the development of EMS. The treatment of EMS remains a challenge. Antioxidant therapies for effective management of reactive oxygen species and inflammation have generated considerable research interest. Antioxidant agents such as Vitamins C and E, resveratrol, curcumin, melatonin, epigallocatechin-3-gallate, and others have been studied for the treatment of EMS. This review presents the role of OS in pathophysiology of EMS and the antioxidant therapies in its management.
Keywords: Antioxidant; Endometriosis; Oxidative Stress; Reactive Oxygen Species; Treatment
|How to cite this article:|
Baboo KD, Chen ZY, Zhang XM. Role of oxidative stress and antioxidant therapies in endometriosis. Reprod Dev Med 2019;3:170-6
| Introduction|| |
Endometriosis (EMS) is a chronic, estrogen-dependent benign inflammatory disease characterized by the presence of endometrial tissue outside the uterine cavity. EMS is a prevalent gynecological disease. It affects approximately 10% of women of reproductive age, up to 80% of women with pelvic pain and 20%–50% of women with infertility. The exact pathogenesis is not known, and the treatment of EMS remains a challenge. EMS is associated with hormonal imbalances and inflammation. Accumulating evidence indicates that oxidative stress (OS) plays an important role in the etiology of EMS., It is reported to play an active role in the initiation, maintenance, and progression of the disease. The available medical treatment includes nonsteroidal anti-inflammatory drugs, combined oral contraceptives, progestins, gonadotropin-releasing hormone agonists, and danazol. The long-term use of hormonal agents often causes adverse effects, and recurrence of symptoms upon cessation of medication is common. In addition, existing therapeutic interventions remain suboptimal, making women who wish to conceive with the choice between pursuing pregnancies and managing their pelvic pain. Novel treatments with minimal adverse effects with long-term use and without adversely affecting fecundity are highly desirable. With the advancing understanding of the cell biology of EMS, medical therapy is increasingly evolving from strategies that focus on the suppression of the hypothalamic–pituitary–ovarian endocrine axis to approaches that target alternative pathways such as OS and inflammation. This review presents the role of OS in pathophysiology of EMS and the antioxidant therapies in its management.
| Oxidative Stress in the Pathophysiology of Endometriosis|| |
OS results from an imbalance between prooxidants (free radical species) and antioxidants. Free radical species including reactive oxygen species (ROS) and reactive nitrogen species are unstable and highly reactive molecules. They bind to cell structures such as nucleic acid, lipids, proteins, and carbohydrates resulting in cellular damage and diseases. Cells possess a wide range of antioxidant systems that scavenge and deactivate excessive free radicals in an attempt to prevent cell damage. Enzymatic antioxidants consist of superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx), and nonenzymatic antioxidants include Vitamin C, Vitamin E, heme, taurine, glutathione (GSH), carotenoids, Vitamin A, selenium, and zinc. OS in EMS may be induced by disruption of the balance between ROS production and the level of antioxidants. Over the past 20 years, growing evidence suggests that OS is a potential key factor involved in the initiation and progression of EMS., A recent study reported that elevated levels of OS positively correlate with the severity of EMS.
EMS is a chronic inflammatory disease, and alterations in the immune system play an important role in its pathogenesis. Substantial evidence suggests that inflammation triggers OS in numerous components of the peritoneal cavity (PC), peritoneal fluid (PF), endometriotic lesions, and peritoneum of women with EMS.,, The macrophages, eosinophils, and neutrophils in endometrial lesions lead to the production of free oxygen radicals that initiate OS in the PC. Due to an inefficient or overwhelmed local immune system, several immunological components of the PF of women with EMS, including increased phagocytic macrophages/monocytes; natural killer (NK) cells; cytotoxic T lymphocytes; and B cells or inflammatory mediators such as prostaglandins, metalloproteinases, cytokines, and chemokines, also create a dynamic milieu of inflammatory and nociceptive mediators, which, in turn, generate higher amounts of ROS. In addition, the transcription factor nuclear factor kappa-B (NF-κB) plays a critical role in triggering inflammation associated with EMS. It is released from macrophages and is elevated due to iron overload in EMS.,
Iron homeostasis in the PC may be disrupted in EMS by the direct impact of hemoglobin derivatives and/or the formation of a proinflammatory and prooxidative environment. Retrograde menstruation is likely to carry highly prooxidant factors, such as heme and iron, into the PC, as well as apoptotic endometrial cells, which are well-known inducers of OS. The free or catalytic form of iron mediates ROS production via the Fenton reaction and induces OS. Recent studies have provided evidence of iron overload in various components of the PC of affected patients, including PF, macrophages, peritoneal tissue, and endometriotic lesions. Iron toxicity might catalyze the production of free radical damaging species, inducing deregulation of cellular processes, cell dysfunction, and apoptosis or necrosis through lipid peroxidation, protein, and DNA damage.,, Iron overload stimulates the NF-κB pathway and increases intercellular adhesion molecule-1 (ICAM-1) expression and soluble ICAM-1 secretion, thereby promoting EMS. Both iron and NF-κB are clearly involved in the development of EMS and both seems to be correlated with one another.
Recent studies have reported a role for epigenetic modifications in ROS-induced OS in EMS. OS may partly mediate changes in epigenetic marks such as DNA methylation and histone modifications. Abnormal DNA methylation in EMS affects the expression of several genes, including homeobox A10, catechol-O-methyltransferase, estrogen receptor beta (ERβ, ESR2), steroidogenic factor 1 (NR5A1), and aromatase (CYP19A1). These genes could alter steroid signaling and responsiveness and are critically involved in development and decidualization. Furthermore, iron oxidation blocks the catalytic activity of the jumonji gene (JMJ, also known as JARID2). ROS oxidizes Fe 2+ to Fe 3+, thereby attenuating the activity of JMJ histone demethylases. Another epigenetic enzyme utilizing Fe 2+ is a member of the ten–eleven translocation (TET) family of hydroxylases. Members of the TET protein family play roles in the DNA methylation process and gene activation. TET-mediated DNA demethylation may protect against OS. TET1, TET2, and TET3 are downregulated in EMS.
The markers of OS increased and the markers of antioxidants decreased in EMS. Leconte et al. showed for the 1st time that deep infiltration EMS is related to an increase of OS and the higher levels of ROS induced the activation of the mechanistic target of rapamycin/protein kinase B, mTOR/AKT pathway. In addition, a large study by Santulli et al. demonstrated that protein OS markers (thiols, advanced oxidation protein products, protein carbonyl, and nitrates/nitrites) were elevated in the PF of women with deep EMS based on surgical classification compared to that of the controls. The PF of EMS patients contains increased concentrations of lipid peroxidation products including malondialdehyde (MDA), 8-isoprostane, lysophosphatidylcholine, and 25-hydroxycholesterol. The concentration of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a sensitive indicator of free radical-induced DNA damage, is higher in the normal ovarian cortex surrounding endometriomas. Polak et al. observed higher PF 8-OHdG and 8-isoprostane concentrations in patients with advanced stages of EMS, compared with patients with nonendometriotic cysts. In addition, expression of 8-oxoguanine DNA glycosylase was found to be significantly lower in patients with EMS. ROS are second messengers of cellular proliferation and are related to the formation and progression of EMS.
Studies show that ROS plays an important role in EMS-related pain and infertility. The mechanism of EMS-related pain remains unclear. Prostaglandins are key mediators of pain and potent activators of nociceptors. Cytokines and OS could induce the production of prostaglandins., In addition, oxidants such as superoxide, nonenzymatic oxidatively modified lipoproteins, and nitric oxide (NO) also play a role in nociception in EMS. These can alter the expression of inflammatory and nociceptive genes. ROS act as signaling molecules and can modify reproductive processes such as tubal function, oocyte maturation, and folliculogenesis. OS can directly or indirectly compromise the oocyte quality in women with EMS. Evidence shows that women with EMS have higher OS compared with healthy fertile women. Women with EMS-associated infertility showed lowest SOD, GPx, and TAC status and highest LPO level in the PF when compared with women with idiopathic infertility and fertile controls. A recent study reported an increase OS status of FF in follicles surrounding endometriomas. Similarly, Da Broi and Navarro found increased follicular 8-OHdG, an indicator of oxidative DNA damage in the follicular fluid (FF) of women with EMS,, and this may be related to compromised oocyte quality. Minimal/mild rather than moderate/severe EMS is more likely associated with a reduced fertilization rate in EMS-related infertility. Several studies have also reported that women with EMS-associated infertility have significantly lower concentrations of antioxidant components such as Vitamin A, Vitamin C, Vitamin E, SOD, and selenium in their FF and/or serum/plasma.
| Antioxidants Targeting Oxidative Stress in Treatment of Endometriosis|| |
The main mechanisms of antioxidant therapy and drug types including vitamins and phytochemicals (polyphenols and flavonoids) and hormonal have been studied in EMS.
Vitamins E and C
Vitamin E is a powerful lipid-soluble antioxidant and consists of a mixture of tocopherols (TOCs) and tocotrienols subgroups. Vitamin E can prevent or delay chronic diseases, especially those believed to have an OS component such as cardiovascular diseases, atherosclerosis, and cancer. Vitamin C is a water-soluble, physiological antioxidant of major importance for protection against diseases caused by OS. Vitamin C plays a key role in preventing lipid peroxidation, and it also helps regenerate reduced antioxidative TOC from TOC radical. The antioxidant Vitamins E and C may be involved in clearing free radicals and ROS which have been implicated in the growth and adhesion of endometrial cells in the PC in women with EMS. The effects of Vitamins C and E in EMS have been studied either alone or in combination. In an experimental rat model, Vitamin C was found to effectively decrease the volume of endometriotic implants, as well as induction of implant volumes in the group which had received continuous Vitamin C. The histopathological structure, however, did not show any significant difference in both the treatment groups, probably because of the short duration (42 d) of treatment. Another report further demonstrated a significant reduction in volume and weight of endometriotic cysts as well as the NK cell content with Vitamin C supplementation in a dose-dependent manner. In a randomized placebo controlled trial (RCT), Santanam et al. randomly assigned 59 women with pelvic pain and EMS and/or infertility into two groups to receive either a combination of Vitamin E (1,200 IU) and Vitamin C (1,000 mg) or placebo daily for 8 weeks prior to surgery. After treatment, a decrease in chronic pelvic pain and PF inflammatory markers (RANTES, interleukin-6 [IL-6], and monocyte chemotactic peptide-1 [MCP-1]) was noted in women receiving the combination of vitamins compared with women receiving placebo. In addition, a large, prospective cohort study reported the inverse association of Vitamins E and C from food intake in EMS, which could be due to the potential mechanisms of micronutrients in minimizing OS involved in the disease. In a randomized, double-blind trial, 34 women with EMS received a bar containing Vitamins C and E (343 mg and 84 mg, respectively) or placebo for 6 months. Mier-Cabrera et al. reported significantly decreased levels of MDA and lipid hydroperoxides (LOOHs) after 4 and 6 months of treatment in patients treated with Vitamin C and E compared to those receiving a placebo. However, it did not improve the pregnancy rate during or after the intervention.
Numerous studies have shown worse outcomes in patients with EMS who undergo in vitro fertilization (IVF) compared with those without, most likely because of lower oocyte quality. An explanation to the lower pregnancy rate and poorer egg quality in these patients may be OS in EMS-related infertility. The lower levels of antioxidant components such as Vitamins A, C, and E and SOD in the FF surrounding mature oocytes before ovulation can affect reproductive performance in patients with EMS., In a recent RCT, the effect of Vitamin C (1,000 mg/d; oral supplementation) on the outcomes of IVF-embryo transfer (IVF-ET) was investigated in patients with EMS. In total, 245 patients with EMS and 132 patients without EMS underwent successful IVF-ET and follow-up, and their serum and FF antioxidant components were compared before and after treatment. Two months posttreatment, serum and FF Vitamin C levels were significantly increased whereas OS markers (ROS, TAC, SOD, and MDA) were unaffected. The treatment with Vitamin C did not affect OS markers in patients with EMS.
Resveratrol (trans-3, 5, 40-trihydroxystilbene [RVT]) is a plant-derived polyphenolic phytoalexin found in high concentrations in the skin of grapes, red wine, berries, and nuts. RVT has antineoplastic, anti-inflammatory, and antioxidant properties in diseases. In recent years, many studies have been conducted to verify the effect of RVT on EMS and to elucidate the mechanism of action. RVT exerts its antioxidant effect through increased expression of SOD, GPx, glutathione-S-transferase, nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase 1 (NQO1), and heme oxygenase-1, and heme oxygenase-1. In mice models of EMS, RVT showed significantly reduced endometriotic implant volumes compared with controls and significant increase in SOD and GPx activities in a dose-dependent manner in the serum and tissue in the RVT (10 mg/kg) and RVT (100 mg/kg) groups. Similarly, MDA and CAT levels were significantly higher in the RVT (100 mg/kg) group compared with controls. Histological scores and proliferating cell nuclear antigen expression levels were also reduced in the RVT groups compared with the control group. Several studies have also demonstrated the anti-inflammatory, antiadhesion, anti-invasion, antiangiogenic, antiproliferative, and proapoptotic activities of RVT in EMS. Both eutopic and ectopic endometrial tissues in women with EMS overexpress ER alpha (ERα, ESR1) and ERβ (ESR2). RVT is a phytoestrogen and can act on both ERs types through different mechanism of actions. Decreased expression of both ESR1 and Ki-67 in endometrial epithelial cells in a dose-dependent manner of activity of Ki-67 was reported in an experimental study in which mice were treated with estradiol (E2) and RVT (60 mg). RVT acts as an agonist and antagonist of estrogen in low and high concentrations, respectively, when combined with estrogen. The suppression of aromatase and cyclooxygenase-2 (COX-2) expression in the eutopic endometrium appears to be an important prerequisite for the effective control of EMS-related pain. Because estrogen is known to upregulate COX-2, counteracting estrogen synthesis in the endometrium normally requires an enzymatic reaction catalyzed by aromatase, and therefore, the inhibition of the aromatase is essential. In a small, nonrandomized, open-label study, 30 mg RVT to the contraceptive regimen was given to 12 patients, who failed to obtain pain relief from COC, and after 2 months of use of combined COC and RVT, 82% of patients had complete resolution of dysmenorrhea and pelvic pain. RVT can potentiate the effect of oral contraceptives in improving EMS-associated dysmenorrhea by decreasing aromatase and COX-2 expression in the endometrium. In a randomized, double-blind, placebo-controlled trial of 44 patients, the effect of RVT 40 mg/d combined with a monophasic COC was compared to COC alone for 42 days in women with EMS. No difference was observed in pain scores whereas serum CA-125 was significantly reduced in both the treatment groups. The difference in results was likely due to different methodologies including length of treatment, pain score scales, or statistical analysis used in the studies. RVT has been shown to potentiate the effects of other medications (e.g., simvastatin); therefore, the combination of RVT with other agents (e.g., leuprolide acetate, LA) should be exercised cautiously because the latter could reduce their therapeutic effects when used together. Based on its diverse properties, RVT seems to be a great potential agent to treat EMS. More studies are necessary to better understand the exact mechanism of action of RVT in EMS, as well as clinical trials with larger sample size are encouraged to evaluate its effectiveness and long-term safety in patients.
Turmeric, obtained from the rhizomes of Curcuma longa, is an important spice all around the world. Curcumin is the principal polyphenol isolated from turmeric, and it possesses diverse pharmacological properties such as antioxidative, anti-inflammatory, anticarcinogenic, and antibacterial. Nanoparticulate (NP) drug delivery system is increasingly explored as an alternative option for the development of new class of drugs for EMS. In an attempt to circumvent the pitfalls of poor solubility, curcumin nanoparticles (Cur-NPs) have been developed. The effect of Cur-NPs with and without letrozole nanoparticles (Let-NPs) was investigated in an experimental EMS model. The study revealed a significant reduction in ROS and lipid peroxidation (LPO) and increase in TAC after administration of Let-Cur (Let-Cur-NPs) and Cur (NP) in mice with EMS compared with endometriotic mice injected with 0.9% NaCl control. Another study demonstrated that Cur caused regression in endometriotic lesions by inhibiting matrix metalloproteinase-9 (MMP-9) activity and expression. The attenuated activity of MMP-9 was associated with decreased expression of tumor necrosis factor-α (TNF-α). Cur treatment further prevented lipid peroxidation and protein oxidation in the endometriotic mice. In addition, Cur was found to cause regression of EMS by inhibiting NF-κB translocation and MMP-3 expression. Cur inhibited the expression and activation of MMP-2, upregulated the expression of TIMP-2, and downregulated the expression of membrane type 1 MMP. A decrease in endometrial stromal cells, cell growth, volume, and weight of endometriotic foci and estradiol levels as well as a decrease in microvessel density were demonstrated by experimental studies., In addition, Cur showed marked suppression of TNF-α-induced expression of ICAM-1 and vascular cell adhesion molecule-1. It also markedly inhibited TNF-α-induced secretion of IL-6, IL-8, and MCP-1 and inhibited the activation of transcription factor NF-κB in human endometrial stromal cells. Deferoxamine is an iron-chelating agent that is used to remove iron from the blood. In a rat model of EMS, Cur and/or deferoxamine contributed to a reduction in implant size and cell proliferation. Another study also showed that Cur could suppress expression of certain cytokines through the NF-κB signaling pathway. This may suggests that Cur has therapeutic potential to reduce inflammation associated with EMS.
Melatonin is a powerful, direct, free radical scavenger and its potent antioxidant effects are well established. Melatonin is a hormone synthesized from tryptophan in the pineal gland during the night. It has multiple effects on a number of different physiological processes and regulates a variety of important central and peripheral processes related to circadian rhythm and reproduction. It scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, NO, and peroxynitrite anion. Its strong potent antioxidant effects are due to the interaction of melatonin with reactive species generating further free radical scavenger intermediates, and this phenomenon is called the free radical scavenging cascade reaction of the melatonin family. It stimulates a number of antioxidative enzymes such as SOD, GSH-Px, GR, and CAT. It also stabilizes microsomal membranes and helps them resist oxidative damage. Mounting evidence supports the anti-inflammatory, antioxidant, analgesic, and vasorelaxant effects of melatonin. A series of animal studies have demonstrated the potential therapeutic effect of melatonin on EMS through observation of a significant reduction in lesion size and other EMS-related markers.,, For example, melatonin effectively decreased endometriotic explant volumes and histopathologic scores in rat models. In the melatonin-treated group, the levels of MDA and COX-2 of endometriotic explants and tissue were significantly decreased whereas the activation of SOD and CAT was significantly increased compared with that of the control group. Compared with Let, an aromatase inhibitor, melatonin treatment resulted in a greater regression of endometriotic foci. Melatonin treatment caused significant increases in SOD and CAT levels, and the recurrence rate was also lower in the melatonin group compared to the Let group after cessation of treatment. An important mechanism of melatonin to reduce the OS is through the downregulation of MMPs. In mouse model experiments, melatonin treatment caused regression of peritoneal EMS by downregulating the activity and expression of MMP-9 and MMP-3 and by increasing TIMP-1 expression. The authors also reported the protective effect of melatonin though inhibition of lipid peroxidation and protein oxidation in the endometrial tissue. Activity of SOD and TIMP-2 staining in the melatonin treatment group was significantly higher whereas significant reductions were observed in implant levels of vascular endothelial growth factor (VEGF) and MMP-9 in the melatonin group compared to that of the control group. In another study, treatment of endometrial implants (10 or 20 mg·kg −1·d −1) with different doses of melatonin in oophorectomized rat experimental models resulted in regression of endometriotic lesions by improving histologic scores in a dose-dependent manner. In a phase II, randomized, double-blind, placebo-controlled trial, Schwertner et al. demonstrated a significant reduction in dysmenorrhea and dysuria, and sleep quality was also improved with melatonin treatment. Moreover, a reduction in the use of analgesic agents and brain-derived neurotrophic factor levels related to improved pain relief were reported. Accumulating studies have shown that exogenous melatonin application can suppress EMS ectopic lesions, relieve pelvic pain, and improve sleeping quality of women with EMS.
Epigallocatechin-3-gallate (EGCG) is the major flavonoid of Camellia sinensis, which is used to produce tea. EGCG is the one of the most abundant polyphenols found in green tea. Several studies have demonstrated its potent antioxidative, antiangiogenic, and apoptotic properties in numerous diseases. EGCG inhibited microvessels in endometriotic implants and suppressed VEGR and VEGR receptor expression through c-JUN, interferon-γ, MMP-9, and chemokine (C-X-C motif) ligand 3 pathways for endothelial proliferation, inflammatory response, and mobility both in experimental EMS in vivo and endometrial cells in vitro. EGCG inhibited estradiol-induced activation, proliferation, and VEGF expression of endometrial cells in vitro and inhibited angiogenesis and blood perfusion in an experimental EMS model. Furthermore, EGCG treatment induced regression of endometriotic lesions histopathologically. EMS is characterized by dense fibrous tissue surrounding the endometrial glands and stroma histologically. Accordingly, the antifibrotic effect of EGCG on EMS has been assessed and resulted in inhibition of cell proliferation, migration, and invasion of endometrial tissue partially due to inhibition of the ERK1/2 and/or JNK signaling pathways, inhibition of phosphorylation of Smad2/3, and decreased fibrotic markers transforming growth factor β1, preventing progression of fibrosis. EGCG has some limitations when used in its native form such as marked unstableness and poor bioavailability. Therefore, in addition to EGCG, a prodrug of EGCG (pro-EGCG, EGCG octaacetate) has been utilized to enhance the stability and bioavailability of EGCG to investigate its potent antiangiogenic effect in experimental EMS mouse models. Both EGCG and pro-EGCG significantly inhibited the development and growth of lesion size and weight while pro-EGCG caused greater inhibition of all angiogenic parameters and had better bioavailability and antioxidative and antiangiogenic capacities compared to that of EGCG.
Other antioxidants such as naringenin, alpha-lipoic acid, n-acetylcysteine, dexpanthenol, hesperidin/nerolidol, and Euterpe oleracea Mart. (Açai) may be effective in the treatment of EMS by antioxidant mechanisms. Only limited studies are available. Have been proven to be efficacious in animal studies, but they have not yet been tested in clinical researches.
| Conclusion|| |
A close relationship between OS and EMS is well documented in the literature. Numerous preclinical studies have demonstrated that some antioxidants could effectively decrease the OS status and reduce endometriotic lesions. Limited clinical researches present the effect of antioxidants in alleviating pain. No promising effect of fertility improvement was reported. Few studies reported the low side effect profiles of these antioxidants. Due to lack of the understandings of the exact mechanism of action, bioavailability, and adverse effects, especially with long-term use, of antioxidants in treating EMS, further investigations are required. Besides, with most of existing studies being preclinical, clinical trials are encouraged to achieve more conclusive results.
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Conflicts of interest
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