Oxidative Damage May Underlie Infertility Associated With Endometriosis, Review Study Finds

Oxidative Damage May Underlie Infertility Associated With Endometriosis, Review Study Finds

Studies have suggested that infertility linked with endometriosis is the result of inflammatory-driven oxidative damage to  eggs, sperm or embryos caused by retrograde menstruation (the backward flow of menstrual blood). A recent review looks at the scientific data supporting that hypothesis, and discusses the results of recent studies testing if treatment with antioxidants like N-acetylcysteine may prevent the damage and improve fertility in patients with endometriosis.

The review, “Endometriosis Is a Cause of Infertility. Does Reactive Oxygen Damage to Gametes and Embryos Play a Key Role in the Pathogenesis of Infertility Caused by Endometriosis?,” was published in the journal Frontiers in Endocrinology.

The exact cause of endometriosis is not well understood, but multiple factors are thought to contribute to its development.

Several explanations for the origin of endometriosis have been proposed: retrograde menstruation, the most discussed one, (when menstrual blood flows backward into the fallopian tubes, the tubes that connect the ovaries to the uterus, and the abdominal cavity); celomic metaplasia (when normal abdominal cells convert to endometrial-like cells); altered immunity (when a malfunction of the immune system promotes the growth of endometrial tissue in the abdomen); when stem cells that implant in the abdominal cavity give rise to endometrial tissue, and: familial inheritance (genetics).

Infertility is a frequent problem associated with endometriosis. Several studies have shown that women with this disease have a lower quality and number of oocytes (immature eggs) and embryos, have reduced implantation and pregnancy rates, and experience miscarriages more often.

Some researchers propose that infertility associated with endometriosis is caused by oxidative stress triggered by retrograde menstruation over endometrial tissues in the abdominal cavity, fallopian tubes or the ovaries.

Retrograde menstruation puts these tissues in direct contact with refluxed blood containing tissue debris and iron released from red blood cells. This may trigger an inflammatory response that induces the release of potent oxidative agents called reactive oxygen species (ROS), produced by specific inflammatory cells called macrophages and neutrophils.

Prior research has shown that ROS (in specific the superoxide anion and hydroxyl radical) can damage DNA, proteins, fats and sugars that make up oocytes, sperm and embryos and lead to aberrant DNA and cell replication, irreversible injury or death of these cells.

The buildup of ROS in the abdomen, fallopian tubes and ovaries — regions with close proximity to oocytes, sperm and embryos — may irreversibly damage them, adversely affecting fertility.

An observation, sustained by different studies, in support of this theory is that peritoneal fluid (fluid in the abdominal cavity) and fallopian fluids of women with endometriosis have stronger pro-oxidant activity and more likely to expose gametes and embryos to oxidative stress.

Other studies also showed that fluids from women with endometriosis cause DNA damage to human sperm and block the maturation of mouse and bovine oocytes cultured in the laboratory (in vitro studies).

Importantly, it has been demonstrated that adding antioxidants to endometriosis fluids can prevent much of the oxidative damage caused to sperm, oocytes and embryos. Those results have prompted researchers to start testing if treatments with antioxidants could improve fertility and reduce cysts (endometriomas) in animal models and in human clinical trials.

In animal studies, a number of well-known antioxidants — vitamins C and E, N-acetylcysteine, resveratrol and melatonin — have been shown to reduce the numbers and sizes of endometriomas.

In humans, one study tested the effects of vitamins C and E supplementation, but had insufficient statistical power from which to draw solid conclusions, and no clinical studies have been reported for resveratrol or melatonin.

“To date the studies with NAC [N-acetylcysteine] have progressed the most toward therapeutic potential,” the authors wrote.

One clinical trial evaluating the benefits of N-acetylcysteine treatment in women with endometriosis showed promising results. A three months treatment with N-acetylcysteine (600 mg three times a day, three consecutive days a week) significantly prevented the growth of endometriomas and reduced the size of others, when compared with women not receiving the treatment. N-acetylcysteine was well-tolerated by all patients and no adverse reactions were reported.

Although this study did not evaluate infertility parameters, it suggests that antioxidants also may prevent the progression of endometriosis, which may affect the quality of gametes and embryos indirectly.

“Future studies will further elucidate the roles of ROS in gametic and embryonic dysfunction and aneuploidy [abnormal number of chromosomes] in infertility caused by endometriosis,” researchers noted in the review study.

The quest for therapies to prevent ROS damage on these processes will continue, they added.

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