Oxidative Stress and Endometriosis

Fig. 4.1
Retinoid levels in endometriosis. HNP1 human neutrophil peptide, MCP monocyte chemotactic protein, TNF tumor necrosis factor, GF Growth factor, IL Interleukin
Several studies have discussed the origin of endometriosis based on the most obvious feature that is associated with it—the presence of the inflammatory reactions. There are several inflammatory cytokines that are present in the endometrium, such as, interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), and TNF [22]. These cytokines activate peritoneal fluid leukocytes. Therefore, cytokines play a role in initiating the formation of endometrial tissues [17]. The spread of these tissues result from a cell-cell and cell-tissue bindings that are caused by the activation of the transcriptional factor kB and the activator protein 1 by various free radicals such as nitric oxide and hydrogen peroxide [23]. The pro-inflammatory cytokines play a key role in the recruitment of phagocytic cells which are noted to produce ROS [24].
Heme and iron are pro-oxidant components that enter the peritoneal cavity during retrograde menstruation, contributing to the oxidative stress recorded in the peritoneal cavity of women with endometriosis [25]. Some studies have reported higher levels of oxidative stress markers in the peritoneal cavity of women with endometriosis [24].
Carvalho et al. studied the total antioxidant capacity in endometriotic patients and concluded that a decreased level of DNA repair activity contributes to the progression of the disease [26]. ROS is also associated with cell adhesion [25].
The peritoneal fluid of women with endometriosis contains increased levels of white blood cells and macrophages, and increased activation of these macrophages release higher levels of pro inflammatory cytokines such as Interleukin-1 (IL-1), Interleukin-6 (IL-6), and Tumor necrosis factor alpha (TNF-α). These cytokines, in turn, stimulate other cytokines and chemokines like Interleukin-8 (IL-8) and RANTES (regulated upon activation, normal T-cell expressed and secreted) [12].
RANTES potentially attracts and activates macrophages, T-lymphocytes and eosinophils [27]. IL-8 promotes angiogenesis. Both IL-6 and TNF-α promote proliferation, adhesion of endometrial cells, and formation of new blood vessels [12]. IL-1, TNF-α and IL-6, also induces the expression of the enzyme aromatase and 17β-hydroxysteroid dehydrogenase levels in endometriotic lesions [28].

4.3 Mechanistic Pathway Connecting Oxidative Stress and Endometriosis

The passage of iron, apoptotic endometrial tissue, and desquamated menstrual cells into the peritoneal cavity through retrograde menstruation induces inflammation. Elevated levels of pro-inflammatory factors triggers the immune system, particularly recruiting and activating granulocytes and macrophages [29]. These cells significantly elevate ROS. Several studies have noted the association between the elevated ROS markers and endometriosis [25].

4.4 Nitric Oxide and Endometriosis

Nitric oxide (NO) is a free radical gas that is soluble in lipids. NO forms during the transformation of l-arginine to l-citrulline under the effect of the nitric oxide synthase (NOS) enzyme [30]. There are three forms of NOS enzymes: neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS). These different forms of enzymes help in the production of nitric oxide (NO). Minute amounts of NO are necessary for various functions such as optimal ovarian function and oocyte implantation [6] but high levels of NO can affect gametes, embryos, and fertility [30]. Moreover, one study suggested that there is an association between fertility and NO levels. Fertilization usually occurs in the ampulla of the oviduct, and the oviduct lumen is adjacent to the peritoneal cavity. Normally, endometrial peritoneal cavity macrophages migrate to the lumen of the oviduct where they increase NO production. This is considered the main reason for reduced fertility in women with endometriosis—iNOS expression.
Research also suggests that iron overload-induced macrophage apoptosis leads to overproduction of NO. Elevated levels of NO might play a significant role in the further establishment and growth of endometriotic lesions [31].

4.5 Is Oxidative Stress a Cause or Effect of Endometriosis?

Oxidative stress is strongly correlated with the presence of endometrial tissues outside the uterine cavity. There is a growing body of evidence discussing the generation of oxidative stress both locally and systemically in patients with endometriosis. Oxidative stress can generate inflammation in the peritoneal cavity through various pathways. Oxidative stress modulatory genes play essential roles in initiating inflammatory reactions and forming new nerve fibres and blood vessels. Researchers are still questioning whether the use of antioxidants, specifically vitamins C and E, significantly improves the number of pregnancies. Therefore, more original, laboratory based research is necessary.
Several clinical trial studies produced varying results regarding the effect of fruits, vegetables, and meat intake on endometriosis. More studies are recommended to determine the best dietary interventions that will help decrease the risk of endometriosis.

4.6 Measurement of Oxidative Stress Markers

1.
Most antioxidants in the body contain organic compounds called thiols. These compounds defend against free radical-induced DNA damage. In one study, thiol levels were significantly lower in 67 women with pelvic endometriosis who underwent laparoscopy than in 41 women without pelvic endometriosis who underwent tubal ligation, suggesting that oxidative stress is likely present in women with endometriosis [32].
 
2.
8-hydroxy-2-deoxyguanosine (8-OHdG) is one of the most important biomarkers of DNA damage caused by free radicals and is a likely marker of carcinogenesis. Isoprostanes are isomers of prostaglandins that are formed during the per-oxidation of arachidonic acid in cell membranes by free radicals. They are considered reliable markers of oxidative stress. A study found that 8-OHdG and 8-isoprostane levels were higher in the peritoneal fluid of patients with endometriosis than in fluid from the reference groups. A statistically significant positive correlation was found between 8-OHdG and 8-isoprostane levels in peritoneal fluid (R = 0.3; P < 0.01). Women with severe endometriosis experienced higher oxidative stress and had higher levels of free radical-induced DNA damage, and hence higher levels of 8-OHDG and 8-isoprostane levels [3].
 
3.
A prospective study was conducted in Brazil to compare the serum markers of oxidative stress in infertile patients with those from endometriosis and infertile patients without endometriosis in order to find a correlation between the levels of these markers and the stage of the disease. The serum markers assessed in the study included malondialdehyde, glutathione, hydroxyperoxide and vitamin E levels. Blood samples were collected, and the levels of these markers were assessed using spectrophotometry and high performance liquid chromatography and compared with the control group. The study showed a positive association between the levels of hydroxyperoxide and the stage of the disease and a negative association between the levels of vitamin E and glutathione levels and no correlation between the stage of the disease and serum malondialdehyde levels in infertile women with endometriosis when compared to the control group. All these results indicate that people with severe endometriosis have high levels of oxidative stress [33].
 
4.
A cross sectional study was conducted on 66 women of reproductive age who were undergoing laparoscopy. Among them, 45 had histologically and laparoscopically proven endometriosis and 21 women did have not have endometriosis and served as controls. Their serum levels were measured for oxidative stress markers such as heat shock protein (HSP70), HSP70b′, thioredoxin (TRX), and ischemia-modified albumin (IMA). Researchers found that mean serum HSP70b levels were higher in the patients with endometriosis than the controls (0.178 ng/mL, SD 0.103, and 0.135 ng/mL, SD 0.014, respectively). The other markers—heat shock protein 70, IMA, and TRX—did not vary between women with endometriosis and the controls [34].
 

4.6.1 The Function of Thioredoxin (TRX) and Thioredoxin-Binding Protein-2 (TBP-2)

Redox regulators such as TRX help prevent cellular damage caused by oxidative stress. They also play roles in cell proliferation, apoptosis, and control of transcriptional factors such as AP-I and function in fetal growth and blastocyst implantation.
The function and the expression of TRX can be regulated by binding with TRX binding protein-2 (TBP-2) or the endogenous inhibitor vitamin D3 up regulated protein [35]. Moreover, an excessive amount of TBP-2 can lead to growth suppression apoptosis that results in the inhibition of TRX activity [36]. Furthermore, unregulated TRX activity that is caused by oxidative stress can induce the implantation of endometrial cells [37]. These changes can affect its normal expression and that of its binding protein: TBP-2. This results in a reduction of TBP-2 expression and an increase in TRX levels in endometrial cells during the late-secretory and menstrual phases. This can lead to the ectopic growth of endometrial tissues that result in endometriosis. Down-regulation of TBP-2, which functions as antitumor agent, can lead to the unregulated growth of endometrial cells or cancerous cells. Examples of cancers that can be caused by the down-regulation of TBP-2 are bladder cancer, colon cancer, prostate cancer, and breast cancer [38].
Apoptosis can alter homeostasis in human endometrium. The presence of endometrial cells outside the uterine cavity is facilitated by a reduction in apoptosis and an increase in cell proliferation during the late-secretory and menstrual phases. Endometriosis is an estrogen-dependent disease and thus, the expression of TBP-2 is affected by estrogen levels. TBP-2 can inhibit blastocyst implantation and embryo development. Any alteration in TRX and TBP-2 expressions will activate a transcription factor such as NF-kB, which is associated with the formation of macrophages and inflammatory cytokines. This, in turn, leads to the formation of inflammatory tissues, thus resulting in endometriosis [37].

4.7 Role of Antioxidants as a Defense System Against Oxidative Stress

Antioxidant systems play a role in cellular homeostasis as they help neutralize excess ROS. Examples of enzymatic antioxidants are superoxide dismutase, catalase and glutathione reductase. Examples of non-enzymatic antioxidants are vitamin E, vitamin C, glutathione and taurine [39]. In one study, vitamin E and vitamin C antioxidant therapy reduced chronic pelvic pain in 43 % of patients with endometriosis [40]. Antioxidants can be present in various percentages whether combined or independent [41]. Antioxidants play an important role in the inhibition of oxidative stress-induced damage and the reduction of the pelvic pain in patients with endometriosis. Patients with endometriosis have low levels of antioxidants including superoxide dismutase and glutathione peroxidase in their peritoneal fluid compared with healthy women. Both of these antioxidants are key components in neutralizing free radicals [42]. Diet is an essential source of antioxidants in the human body. Women who consume small amounts of fruits and vegetables have a higher risk of developing endometriosis [43].

4.7.1 Vitamins E, A, C and Melatonin as Anti-Oxidants

Many studies have examined the role of vitamin E supplementation in women diagnosed with endometriosis. Malondialdehyde (MDA) is a biomarker that measures the extent of lipid peroxidation. Oral supplementation with vitamin E lowered levels of lipid hydroperoxide (LOOH) and MDA in the peripheral blood in patients with endometriosis [44] and also lead to a non-significant increase in pregnancy rates. A third of the women who were provided the vitamin E supplementation conceived within 5 months [44].

4.7.1.1 The Role of Vitamin A

Vitamin A is an anti-oxidant that plays an important role in cell growth, immunity, hematopoiesis, and reproduction. It is also important in ovarian follicular growth, oocyte quality, and steroidogenesis [45]. High levels of vitamin A have a negative effect. All-trans retinoic acid (ATRA), which is the active form of vitamin A, plays a fundamental role in oocyte development, and women who have low levels of ATRA can develop inflammation, thus leading to the proliferation of endometrial cells outside the uterine cavity. One factor that may explain why some women develop endometriosis moreso than others is low retinoid metabolism in follicular fluid. This initiates aberrant expressions of ARTA regulated genes, cytokines, matrix metalloproteinases, tumour necrosis factor-B, IL-6, IL-11, several integrins, bax, and fas ligand. In turn, the aberrant expression stimulates the growth and the migration of cells and decreases cell death. These are some of the features that initiate the growth of the endometrial cells (Fig. 4.2).
A331178_1_En_4_Fig2_HTML.gif
Fig. 4.2
Formation of endometrial tissues

4.7.1.2 The Role of Vitamin C

Vitamin C is a water-soluble antioxidant that neutralizes the hydroxyl ion, superoxide ion, and nitrogen radicals. Vitamin C is needed to convert the oxidized vitamin E into its original form. The original recycled form of vitamin E can neutralize ROS [46].
Eight weeks of oral vitamin E and C supplementation significantly reduced levels of inflammatory markers such as RANTES, interleukin-6 (IL-6), and monocyte chemotactic protein (MCP-1) in the peritoneal cavity of women with endometriosis [40]. The study results also showed that after the supplementation with vitamins C and E, pelvic pain during menstruation declined in 43 % of the women [40].

4.7.1.3 Role of Melatonin as an Antioxidant in Endometriosis

Melatonin is an analgesic, antioxidant and anti-inflammatory agent. It has a reverse effect compared with brain-derived neurotrophic factor (BDNF) (Fig. 4.3). Administration reduced pelvic pain caused by inflammation in 39 % of women with endometriosis, even during menstruation, and improved sleep quality [47]. That study also found that the women who used melatonin required fewer analgesics. Melatonin may reduce pain by inhibiting luteinizing hormone (LH) levels, thus obstructing ovulation and increasing progesterone levels. This can explain the antioxidative effect of melatonin in decreasing the pelvic pain that is caused by endometriosis [47].
A331178_1_En_4_Fig3_HTML.gif
Fig. 4.3
Effect of melatonin in endometriosis patients

4.7.2 Studies on Antioxidant Rich Diet in Endometriosis Patients

Diet plays an essential role in reducing the effects of endometriosis. For example, foods that contain fish oil have high levels of polyunsaturated fatty acids (PUFAs), which are rich in omega-3 fatty acids (FAs). These reduce the inflammatory reactions that are present in the endometrium. A study done on mice found that adding fish oils to their diet decreased the size of the lesions caused by endometriosis [48].
However, other diet components have the opposite effect of fish oils, such as palmitic acid, which contains both saturated and trans-unsaturated fats. These components increase the risks associated with endometriosis.
There are varying viewpoints on the effects of fruit and vegetables on endometriosis. Some researchers believe that a dietary rich in fruits and vegetables may increase the risk of endometriosis [49]. On the other hand, Parazzini et al. [43] found that the intake of fruit and green vegetables can decrease the effects caused by the disease. Due to the different opinions regarding the effect of fruits and vegetable on endometriosis patients, more studies need to be performed.

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Jun 25, 2017 | Posted by in GYNECOLOGY | Comments Off on Oxidative Stress and Endometriosis

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