Role of Oxidative Stress and Antioxidant Therapies in Endometriosis

“Resveratrol 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.[52] RVT has antineoplastic, anti‐inflammatory, and antioxidant properties in diseases.”

“Reproductive and Developmental Medicine ¦ September 25, 2019 ¦ Volume 3 ¦ Issue 3 171 and deactivate excessive free radicals in an attempt to prevent cell damage.[7] Enzymatic antioxidants consist of superoxide”

“The available medical treatment includes nonsteroidal anti‐inflammatory drugs, combined oral contraceptives, progestins, gonadotropin‐releasing hormone agonists, and danazol.[4] The long‐term use of hormonal agents often causes adverse effects, and recurrence of symptoms upon cessation of medication is common.”

“Curcumin is the principal polyphenol isolated from turmeric, and it possesses diverse pharmacological properties such as antioxidative, anti‐inflammatory, anticarcinogenic, and antibacterial.[60] Nanoparticulate (NP) drug delivery system is increasingly explored as an alternative option for the development of new clas…”

“OS results from an imbalance between prooxidants (free radical species) and antioxidants.[6] Free radical species including reactive oxygen species (ROS) and reactive nitrogen species are unstable and highly reactive molecules.”

“Vitamin E is a powerful lipid‐soluble antioxidant and consists of a mixture of tocopherols (TOCs) and tocotrienols subgroups.[41]”

“[70] 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.[71] It stimulates a number of antioxidative enzymes such…”

“[69] It scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen, NO, and peroxynitrite anion.[70] Its strong potent antioxidant effects are due to the interaction of melatonin with reactive species generating further free radical scavenger intermediates…”

“Accumulating evidence indicates that oxidative stress (OS) plays an important role in the etiology of EMS.[2,3] It is reported to play an active role in the initiation, maintenance, and progression of the disease.”

“[8,9,11] The macrophages, eosinophils, and neutrophils in endometrial lesions lead to the production of free oxygen radicals that initiate OS in the PC.[12] Due to an inefficient or overwhelmed local immune system, several immunological components of the PF of women with EMS, including increased phagocytic macrophages…”

“fluid (PF), endometriotic lesions, and peritoneum of women with EMS.[8,9,11] The macrophages, eosinophils, and neutrophils”

“ROS oxidizes Fe2+ to Fe3+, thereby attenuating the activity of JMJ histone demethylases.[25] Another epigenetic enzyme utilizing Fe2+ is a member of the ten–eleven translocation (TET) family of hydroxylases.”

“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.[69] It scavenges a variety of reactive oxygen and nitrogen species including hydroxyl radical, hydrogen peroxide, singlet oxygen,…”

“Vitamin C plays a key role in preventing lipid peroxidation, and it also helps regenerate reduced antioxidative TOC from TOC radical.[42] The antioxidant”

“[8,9,11] The macrophages, eosinophils, and neutrophils in endometrial lesions lead to the production of free oxygen radicals that initiate OS in the PC.[12] Due to an inefficient or overwhelmed local immune system, several immunological components of the PF of women with EMS, including increased phagocytic macrophages…”

“[39] Minimal/mild rather than moderate/severe EMS is more likely associated with a reduced fertilization rate in EMS‐related infertility.[40] Several studies have also reported”

“in endometrial lesions lead to the production of free oxygen radicals that initiate OS in the PC.[12] Due to an inefficient or”

“[49] 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.[49,50] In a recent RCT, the effect of Vitamin C (1,000 mg/d; oral supplementation) on the outcomes of IVF‐embryo transfer…”

“[49] 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.[49,50] In a recent RCT, the effect of Vitamin C (1,000 mg/d; oral supplementation) on the outcomes of IVF‐embryo transfer…”

“women receiving the combination of vitamins compared with women receiving placebo.[46] 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”

“Moreover, a reduction in the use of analgesic agents and brain‐derived neurotrophic factor levels related to improved pain relief were reported.[79] Accumulating studies have shown that exogenous melatonin application can suppress EMS ectopic lesions, relieve pelvic pain, and improve sleeping quality of women with EMS.”

“kappa‐B (NF‐κB) plays a critical role in triggering inflammation associated with EMS.[14] It is released from macrophages and is elevated due to iron overload in EMS.”

“Cytokines and OS could induce the production of prostaglandins.[33,34] In addition, oxidants such as superoxide, nonenzymatic oxidatively modified lipoproteins, and nitric oxide (NO) also play a role in nociception in EMS.”

“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.[28] The PF of EMS patients contains increased concentrations of lipid peroxidatio…”

“[29] 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.[30] Polak et al.”

“direct impact of hemoglobin derivatives and/or the formation of a proinflammatory and prooxidative environment.[17] Retrograde”

“[14] It is released from macrophages and is elevated due to iron overload in EMS.[15,16]”

“fluid (PF), endometriotic lesions, and peritoneum of women with EMS.[8,9,11] The macrophages, eosinophils, and neutrophils”

“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.[66] Deferoxamine is an iron‐chelating agent that is used to remove iron from the blood.”

“in epigenetic marks such as DNA methylation and histone modifications.[23] Abnormal DNA methylation in EMS affects the expression of several genes, including homeobox A10, catechol‐O‐methyltransferase,[24] estrogen receptor beta (ERβ, ESR2), steroidogenic factor 1 (NR5A1), and aromatase (CYP19A1).”

“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.[48] However, it did not improve the pregnancy rate during or after the intervention.”

“Accumulating evidence indicates that oxidative stress (OS) plays an important role in the etiology of EMS.[2,3] It is reported to play an active role in the initiation, maintenance, and progression of the disease.”

“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.[80…”

“[74‐76] For example, melatonin effectively decreased endometriotic explant volumes and histopathologic scores in rat models.[77] 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 increase…”

“[80] 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.[81] Furthermore, EGCG treatment induced regression of endometriotic lesions histopathologically.”

“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 transfo…”

“This may suggests that Cur has therapeutic potential to reduce inflammation associated with EMS.[68]”

“fluid (PF), endometriotic lesions, and peritoneum of women with EMS.[8,9,11] The macrophages, eosinophils, and neutrophils”

“[8,9,11] The macrophages, eosinophils, and neutrophils in endometrial lesions lead to the production of free oxygen radicals that initiate OS in the PC.[12] Due to an inefficient or overwhelmed local immune system, several immunological components of the PF of women with EMS, including increased phagocytic macrophages…”

“[8,9,11] The macrophages, eosinophils, and neutrophils in endometrial lesions lead to the production of free oxygen radicals that initiate OS in the PC.[12] Due to an inefficient or overwhelmed local immune system, several immunological components of the PF of women with EMS, including increased phagocytic macrophages…”

“RVT can potentiate the effect of oral contraceptives in improving EMS‐associated dysmenorrhea by decreasing aromatase and COX‐2 expression in the endometrium.[56] 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 f…”

“Reproductive and Developmental Medicine ¦ September 25, 2019 ¦ Volume 3 ¦ Issue 3 174 caused regression of peritoneal EMS by downregulating the activity and expression of MMP‐9 and MMP‐3 and by increasing TIMP‐1 expression.[78] The authors also reported the protective effect of melatonin though inhibition of lipid per…”

“In addition, Cur was found to cause regression of EMS by inhibiting NF‐κB translocation and MMP‐3 expression.[62] Cur inhibited the expression and activation of MMP‐2, upregulated the expression of TIMP‐2, and downregulated the expression of membrane type 1 MMP.”

“[56] 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.[57] No difference was observed in pain scores whereas serum CA‐125 was significantly reduced in both the treatment groups.”

“[8,9,11] The macrophages, eosinophils, and neutrophils in endometrial lesions lead to the production of free oxygen radicals that initiate OS in the PC.[12] Due to an inefficient or overwhelmed local immune system, several immunological components of the PF of women with EMS, including increased phagocytic macrophages…”

“NF‐κB are clearly involved in the development of EMS and both seems to be correlated with one another.[22]”

“Histological scores and proliferating cell nuclear antigen expression levels were also reduced in the RVT groups compared with the control group.[54] Several studies have also demonstrated the anti‐inflammatory, antiadhesion, anti‐invasion, antiangiogenic, antiproliferative, and proapoptotic activities of RVT in EMS.”

“In recent years, many studies have been conducted to verify the effect of RVT on EMS and to elucidate the mechanism of action.[53] RVT exerts its antioxidant effect through increased expression of SOD, GPx, glutathione‐S‐transferase, nicotinamide adenine dinucleotide phosphate: quinone oxidoreductase 1 (NQO1), and hem…”

“mechanisms of micronutrients in minimizing OS involved in the disease.[47] 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.”

“[63] 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.[64,65] In addition, Cur showed marked suppression of TNF‐α‐induced expression of ICAM‐1 and vascular cell adhe…”

“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.[74] An important mechanism of melatonin to reduce the OS is through the downregulation of MMPs.”

“[8,9] A recent study reported that elevated levels of OS positively correlate with the severity of EMS.[10]”

“observed higher PF 8‐OHdG and 8‐isoprostane concentrations in patients with advanced stages of EMS, compared with patients with nonendometriotic cysts.[31] In addition, expression of 8‐oxoguanine DNA glycosylase was found to be significantly lower in patients with EMS.”

“, leuprolide acetate, LA) should be exercised cautiously because the latter could reduce their therapeutic effects when used together.[59] Based on its diverse properties, RVT seems to be a great potential agent to treat EMS.”

“[28] The PF of EMS patients contains increased concentrations of lipid peroxidation products including malondialdehyde (MDA), 8‐isoprostane, lysophosphatidylcholine, and 25‐hydroxycholesterol.[29] The concentration of 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG), a sensitive indicator of free radical‐induced DNA damage, is hi…”

“Reproductive and Developmental Medicine ¦ September 25, 2019 ¦ Volume 3 ¦ Issue 3 172 Da Broi and Navarro found increased follicular 8‐OHdG, an indicator of oxidative DNA damage in the follicular fluid (FF) of women with EMS,[37,38] and this may be related to compromised oocyte quality.[39] Minimal/mild rather than mo…”

“[49,50] 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.[51] In total, 245 patients with EMS and 132 patients without EMS underwent successful IVF‐ET and follow‐up, and their serum and FF antioxidant compo…”

“[35] A recent study reported an increase OS status of FF in follicles surrounding endometriomas.[36] Similarly,”

“It also stabilizes microsomal membranes and helps them resist oxidative damage.[72] Mounting evidence supports the anti‐inflammatory, antioxidant, analgesic, and vasorelaxant effects of melatonin.”

“Cytokines and OS could induce the production of prostaglandins.[33,34] In addition, oxidants such as superoxide, nonenzymatic oxidatively modified lipoproteins, and nitric oxide (NO) also play a role in nociception in EMS.”

“[31] In addition, expression of 8‐oxoguanine DNA glycosylase was found to be significantly lower in patients with EMS.[32] ROS are second messengers of cellular proliferation and are related to the formation and progression of EMS.”

“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.[44] The histopathological structure, however, did not show any significant difference in both”

“adhesion molecule‐1 (ICAM‐1) expression and soluble ICAM‐1 secretion, thereby promoting EMS.[15] Both iron and”

“[75] 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.[76] In a phase II, randomized, double‐blind, placebo‐co…”

“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.[75] In another study, treatment of endometria…”

“[26] TET1, TET2, and TET3 are downregulated in EMS.[27]”

“reduction in volume and weight of endometriotic cysts as well as the NK cell content with Vitamin C supplementation in a dose‐dependent manner.[45] In a randomized placebo controlled”

“, simvastatin);[58] therefore, the combination of RVT with other agents (e.”

“In a rat model of EMS, Cur and/or deferoxamine contributed to a reduction in implant size and cell proliferation.[67] Another study also showed that Cur could suppress expression of certain cytokines through the NF‐κB signaling pathway.”

“[23] Abnormal DNA methylation in EMS affects the expression of several genes, including homeobox A10, catechol‐O‐methyltransferase,[24] estrogen receptor beta (ERβ, ESR2), steroidogenic factor 1 (NR5A1), and aromatase (CYP19A1).”

“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.[43] The effects of Vitamins C and E in EMS have been studied either alone or in”

“)ese vitamins may be considered as neutralizing agents against free radicals and ROS generated by endometriotic cells [27].”

“Since redox dysregulation plays a vital role in the pathophysiology of endometriosis, a considerable number of studies have indicated the positive effects of antioxidants such as vitamin C, vitamin E, resveratrol, curcumin, melatonin, and epigallocatechin-3-gallate (EGCG) as a supplement along with common endometriosi…”

“Tose compounds involved vitamin C, vitamin E, curcumin, resveratrol, fa-vonoids, and epigallocatechin [1, 5, 11, 12].”

“Furthermore, curcumin therapy in mice with endometriosis has been found to protect against LPO and protein oxidation (Baboo et al. 2019).”

“Existing literature on antioxidant therapy indicates that the positive attributes of antioxidants may alleviate symptoms of endometriosis-related pain and mitigate oxidative damage [15].”

“Endometriosis patients have higher ROS levels than healthy, fertile women, according to studies (Baboo et al. 2019).”