Endometriosis and... Oxidative Stress

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https://pubmed.ncbi.nlm.nih.gov/10101808/ Endometriosis: a disease of oxidative stress? - PubMed (nih.gov)

Endometriosis: a disease of oxidative stress?

Abstract

Our central hypothesis proposes that oxidatively damaged red blood cells (RBCs), apoptotic endometrial cells or undigested endometrial tissue may signal the recruitment and activation of mononuclear phagocytes. Women with endometriosis are prone to respond to this stimulus with an inadequate macrophage scavenger receptor response although the secretory response is not impaired. Activated macrophages in the peritoneal cavity generate an oxidative stress, which consists of lipid peroxides, their degradation products, and products formed from their interaction with low-density lipoprotein (LDL) apoprotein and other proteins. The lipoproteins of the peritoneal fluid (interstitial fluid) have been shown to have lower vitamin E levels and to be more readily oxidized than plasma, so peritoneal fluid may actually contribute to the disease process actively rather than as a passive carrier of mediators of inflammation and growth. As a result of such a stress, a sterile, inflammatory reaction with secretion of growth factors, cytokines, and chemokines is generated, which is deleterious especially to successful reproduction. We propose that such a pro-oxidant environment (peritoneal fluid as well as activated macrophages) promotes growth of ectopic endometrium. The data presented in this review are just the beginning of exploring the role of oxidative stress in mediating the pathophysiology of endometriosis. Only by understanding the mechanisms involved in the pathogenesis of endometriosis can we develop the basis for new diagnostic and therapeutic approaches.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472204/ Evaluation of Oxidative Stress and Severity of Endometriosis - PubMed (nih.gov)

Conclusions:

Oxidative stress might play a role in the disease process of endometriosis. Control of oxidative stress can be used as the latest treatment option for the management of endometriosis.

Oxidative stress is one among the many etiologic theories for endometriosis. These biomolecules have generated immense research interest. Oxidative stress is detected when there is an imbalance between the antioxidants and the prooxidants. They have been implicated in over hundred disease conditions.

Studies have suggested that a key inflammatory environment associated with endometriosis is found in peritoneal fluid. Oxidative stress takes place in macrophages and other inflammatory cells of the peritoneal fluid, with cellular debris serving as a substrate. The products derived from this process move to the systemic circulation in serum/plasma. That is why peritoneal fluid might be more vulnerable than serum to the effects of oxidative stress. Moreover, oxidative stress biomarkers in serum may reflect oxidative status which is due to other causes, in addition to endometriosis, whereas in peritoneal fluid, as it is localized, it may give a more accurate result of endometriosis.

Many studies have shown that women with endometriosis have increased peritoneal fluid volumes and number of peritoneal macrophages.

As shown in the results, most of our patients had moderate-to-severe endometriosis. More than 80% of them had presented with infertility as their complaint.

Our study showed lower levels of glutathione peroxidase in severe endometriosis.

Understanding the mechanism of ROS, oxidative stress, cytokines, and growth factor, their production and detoxification in a better way, further investigation of their effects on the peritoneal fluid environment will help us to acquire new insight in this disease. This may lead to the development of novel diagnostic and therapeutic remedies.

Dietary supplementation with antioxidants will be a better potential strategy for long-term management of endometriosis, as it is cost-effective, noninvasive, and there is no fear of toxicity.

The oxidative stress status represents a mechanism which is amenable to treatment or prevention of endometriosis. These novel avenues may help to reduce the health-related morbidity and health-care costs of endometriosis.

Conclusions

The results of this study demonstrate that oxidative stress is present in all patients with endometriosis. Oxidative stress is found to increase with increase in the severity of the disease.

Discovery of new biomarkers for oxidative stress and validation of putative biomarkers are crucial to make progress in the field.

Identification of biomarkers for early noninvasive diagnosis of endometriosis should be identified as a priority. It may also be used to follow the disease progression and for early clinical application.

Hence, antioxidants can be considered as a good treatment option in patients with endometriosis to prevent oxidative stress and in turn prevent the progression of disease process.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405905/ Targeting Oxidative Stress Involved in Endometriosis and Its Pain - PMC (nih.gov)

A comprehensive exploration of previous research revealed that endometriosis is associated with elevated reactive oxygen species and oxidation products, decreased antioxidants and detoxification enzymes, and dysregulated iron metabolism. High levels of oxidative stress contributed to inflammation, extracellular matrix degradation, angiogenesis, and cell proliferation, which may explain its role in endometriosis. Endometriosis-associated pain was attributed to neurogenic inflammation and a feed-forward mechanism involving macrophages, pro-inflammatory cytokines, and pain-inducing prostaglandins.

N-acetylcysteine, curcumin, melatonin, and combined vitamin C and E supplementation displayed promising results for the treatment of endometriosis,

but further research is needed for their use in this population.

The role of oxidative stress in the development and progression of endometriosis has been well-established by our studies and other researchers who have confirmed the presence of elevated oxidative stress markers in comparison to control groups.

4. Treatments for Oxidative Stress

As oxidative stress is one important etiological mechanism for endometriosis, managing oxidative stress may alleviate some endometriosis-associated symptoms and the clinical severity of this condition. Correcting the imbalance between ROS and antioxidants could be beneficial as this imbalance results in increased oxidative stress which augments disease symptoms, tissue destruction, and the progression of endometriosis. Novel and efficacious treatment options must directly target oxidative stress. For the treatment of other diseases, various antioxidants are frequently prescribed to control oxidative stress.

We propose that either a high antioxidant diet or antioxidant supplements may be effective in treating and reducing the severity of endometriosis.

Low antioxidant levels in endometriosis may be due to insufficient dietary consumption of antioxidants. A study conducted by Mier-Cabrera et al., found deficient intake of vitamins A, C, and E in addition to zinc and copper when compared to the control group. Women with endometriosis may benefit from participation in a high antioxidant diet, since this diet could serve to correct the significantly lower levels of antioxidants found in the PF of women with endometriosis. Currently, there seems to be a lack of substantial evidence on the efficacy of antioxidant supplementation in counteracting oxidative stress, which may partially be due to study limitations such as small sample sizes. Some of the antioxidants that have been studied to block oxidative stress in endometriosis are discussed below.

4.1. Vitamins C and E

4.2. Vitamin D and Omega-3 Fatty Acids

4.3. N-Acetylcysteine

4.4. Melatonin

4.5. Curcumin

4.6. Alternative Treatment Options

• dietary weight loss and exercise

• dietary interventions

• flavonoids

• gut microbiota

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https://www.rbmojournal.com/article/S1472-6483(10)62026-3/pdf Role of oxidative stress in endometriosis (rbmojournal.com)

Of the several hypotheses that have been proposed to explain the pathophysiology of endometriosis, OS is one of the leading theories. There is cumulative evidence in animal and human studies that show OS is one of the main processes in the pathogenesis of endometriosis.

OS and infl ammation are closely linked and have been proposed to play a role in the aetiology of both ovarian cancer and endometriosis. The benefi cial effects of antioxidant therapy and immunomodulators need to be investigated in larger studies with adequate statistical power.

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https://www.mdpi.com/1422-0067/24/2/914 IJMS | Free Full-Text | Higher Oxidative Stress in Endometriotic Lesions Upregulates Senescence-Associated p16ink4a and β-Galactosidase in Stromal Cells (mdpi.com)

Conclusions

The current work presents, in a concise manner, the consistent ROS presence in endometriosis, the dysregulation of MAPK expression, and the deleterious impact of ROS on the expression of senescence markers (which was observed in stromal cells from endometriotic tissues). The results demonstrated in this study contribute to the understanding of the cell senescence path in endometriotic lesions and provide insights into the long-term persistence of the disease. The presence of senescent cells in endometriosis, upregulated by consistent ROS and the dysregulation of MAPK, could shift the way we currently treat patients.

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Also,

https://www.buffalo.edu/news/releases/2004/10/6963.html Role of Oxidative Stress in the Menstrual Cycle Focus of Study - University at Buffalo

BUFFALO, N.Y. -- Researchers at the University at Buffalo are conducting the first comprehensive study of the relationship between hormonal changes in the menstrual cycle and cellular oxidative stress, thought to be an important factor in female infertility.

Oxidative stress is caused by highly toxic, highly reactive oxygen molecules called free radicals, which can damage tissues if not neutralized by antioxidants.

"Studies of both humans and animals have suggested that oxidative stress may be implicated in the risk of infertility in both males and females,"

"We think the ways oxidative stress may influence female fertility include its potential impact on the growth of egg follicles in the ovary, its role in the development of endometriosis and its possible regulation of blood vessel formation in the endometrium," said Wactawski-Wende.

"We know that micronutrients in the diet such as vitamins A, C and E, as well as antioxidant enzymes, are able to neutralize oxygen free radicals and inhibit oxidative stress," she said.

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https://www.researchgate.net/publication/341601722_The_role_of_immune_and_oxidative_pathways_in_menstrual_cycle_associated_depressive_physio-somatic_breast_and_anxiety_symptoms_Modulation_by_sex_hormones The role of immune and oxidative pathways in menstrual cycle associated depressive, physio-somatic, breast and anxiety symptoms: Modulation by sex hormones | Request PDF (researchgate.net)

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https://rbej.biomedcentral.com/articles/10.1186/1477-7827-3-28 Role of oxidative stress in female reproduction | Reproductive Biology and Endocrinology | Full Text (biomedcentral.com)

In a healthy body, ROS (reactive oxygen species) and antioxidants remain in balance. When the balance is disrupted towards an overabundance of ROS, oxidative stress (OS) occurs. OS influences the entire reproductive lifespan of a woman and even thereafter (i.e. menopause). OS results from an imbalance between prooxidants (free radical species) and the body's scavenging ability (antioxidants).

There is growing literature on the effects of OS in female reproduction with involvement in the pathophsiology of preeclampsia, hydatidiform mole, free radical-induced birth defects and other situations such as abortions. Numerous studies have shown that OS plays a role in the pathoysiology of infertility and assisted fertility. There is some evidence of its role in endometriosis, tubal and peritoneal factor infertility and unexplained infertility.

The review comprehensively explores the literature for evidence of the role of oxidative stress in conditions such as abortions, preeclampsia, hydatidiform mole, fetal embryopathies, preterm labour and preeclampsia and gestational diabetes. The review also addresses the growing literature on the role of nitric oxide species in female reproduction. The involvement of nitric oxide species in regulation of endometrial and ovarian function, etiopathogenesis of endometriosis, and maintenance of uterine quiescence, initiation of labour and ripening of cervix at parturition is discussed. Complex interplay between cytokines and oxidative stress in the etiology of female reproductive disorders is discussed. Oxidant status of the cell modulates angiogenesis, which is critical for follicular growth, corpus luteum formation endometrial differentiation and embryonic growth is also highlighted in the review. Strategies to overcome oxidative stress and enhance fertility, both natural and assisted are delineated. Early interventions being investigated for prevention of preeclampsia are enumerated. Trials investigating combination intervention strategy of vitamin E and vitamin C supplementation in preventing preeclampsia are highlighted. Antioxidants are powerful and there are few trials investigating antioxidant supplementation in female reproduction.

7. Conclusion

The literature provides some evidence of oxidative stress influencing the entire reproductive span of a woman, even the menopausal years. OS plays a role in multiple physiological processes from oocyte maturation to fertilization and embryo development. There is burgeoning literature on the involvement of OS in the pathoysiology of infertility, assisted fertility and female reproduction. Infertility is a problem with a large magnitude. In this review we attempted to examine the various causes of female infertility and the role of OS in various etiologies of infertility.

An increasing number of published studies have pointed towards increased importance of the role of OS in female reproduction. Clearly, we have much to learn, but what we do know is that the role of OS in female reproduction cannot be underestimated. There is evidence that OS plays a role in conditions such as abortions, pre-eclampsia, hydatidiform mole, fetal embryopathies, preterm labor and pre-eclampsia and gestational diabetes, which lead to an immense burden of maternal and fetal morbidity and mortality.

We emphasize that free radicals have important physiological functions in the female reproductive tract as well as excessive free radicals precipitate female reproductive tract pathologies.

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https://www.endofound.org/can-endometriosis-increase-your-risk-for-miscarriage Can Endometriosis Increase Your Risk For Miscarriage? | EndoFound

Endometriosis can have an effect on so many areas of your life. You may be concerned about your own fertility, with not only conceiving, but also having a healthy pregnancy and healthy baby. Because endometriosis does affect the reproductive system, you may have questions and concerns when it comes to pregnancy and whether or not you’re at a higher risk for miscarriage. 

https://www.verywellhealth.com/endometriosis-and-pregnancy-5188773 Endometriosis and Pregnancy: Fertility, Gestation, Postpartum (verywellhealth.com)

It’s been estimated that infertility affects 30% to 50% of women with endometriosis.

https://fertilityinstitute.com/blog/can-endometriosis-cause-miscarriage/ A larger systematic review found that endometriosis may increase spontaneous miscarriage risks by 80%. Another study published in Human Reproduction found the following results:

“Four hundred and seventy-eight pregnancies in endometriosis-affected women and 964 pregnancies in controls were analyzed. The previous miscarriage rate was significantly higher in women with endometriosis compared with the controls (139/478 [29%] versus 187/964 [19%], respectively; P < 0.001).”

https://www.verywellhealth.com/cervical-endometriosis-5218036 Cervical Endometriosis: Symptoms, Diagnosis, Treatment (verywellhealth.com)

https://reproductive-health-journal.biomedcentral.com/articles/10.1186/s12978-021-01257-x The role of oxidative stress in patients with recurrent pregnancy loss: a review | Reproductive Health | Full Text (biomedcentral.com)

Results

The search yielded 1116 publications, of which 92 were included in the final analysis. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) at basal levels have various physiological functions whereas deviation from redox window is associated with different pathologies including early pregnancy loss. The currently available studies support the concept that increased oxidative stress (OS) and deficient antioxidant protection is implicated in the etiology of recurrent pregnancy loss (RPL) but underlying mechanisms through which OS affects pregnancy outcome remains largely indefinable.

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https://www.carefertility.com/blog/oxidative-stress-the-main-cause-of-sperm-dna-damage/ Oxidative Stress: the main cause of sperm DNA damage (carefertility.com)

Oxidative stress and male fertility

High levels of oxidative stress have been linked to poor sperm function, abnormal semen analysis results, and failed IVF outcomes. There is evidence that high levels of oxidative stress can cause changes in the sperm cell membranes, affecting their morphology and motility, as well as causing damage to their DNA. This DNA damage could result in DNA errors within an embryo, in turn causing lower pregnancy rates and a higher risk of miscarriage.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512072/ Association of Oxidative Stress on Pregnancy - PMC (nih.gov)

Studies have confirmed that oxidative stress has a significant impact on pregnancy and is involved in the pathomechanism of adverse pregnancy outcomes.

In conclusion oxidative stress is unquestionably linked to abnormalities in both the pregnant mother and fetal development.

https://www.readersdigest.ca/health/healthy-living/3-herbs-and-supplements-take-if-you-re-trying-conceive/

N-acetylcysteine

N-acetylcysteine (NAC) is one of the most studied antioxidant agents for therapeutic treatment.

Other antioxidants":

Resveratrol, Vitamin D3, Vitamin E, Q-10, Zinc, Quercetin, Vitamin C, K2MK7, Beta Carotene, Nigella Sativa, Turmeric, Aronia berry, MSM, guanabana leaves, Herringbone, various herbs…

https://outraged.substack.com/p/treatment-in-practice TREATMENT IN PRACTICE - by OUTRAGED HUMAN (substack.com)