Oxidative stress is known to be involved in a number of pathological conditions, including atherosclerosis, neurodegeneration, cancer and aging. It is also associated with endometriosis and its conversion to EAOC. It causes genetic alterations by inducing stress responsive genes. Some of the genetic alterations include DNA hypo-methylation, telomere shortening, chromosomal aberration, microsatellite instability.

High quantities of iron found within the endometriotic cysts play a vital role in the transformation of endometriosis to EAOC. Free iron due to retrograde menstruation in endometriosis causes persistent oxidative stress and modification of proteins and lipids in the cells, generating free radicals and hypoxia. This leads to extensive DNA damage [18], loss of heterozygosity, and decreased DNA repair contributing to carcinogenesis [19] (Fig. 7.1).

Recent studies have shown HNF-1β overexpression in endometriosis, including both the inflammatory and atypical lesions and within the foci of endometriotic cells. Over expression of hepatocyte nuclear factor-1 (HNF-1 beta) contributes to the formation of clear cell carcinoma under stressful conditions such as oxidative stress. Oxidative stress causes hypo-methylation, which may lead to HNF-1 beta activation and genomic instability, which are evident in clear cell carcinoma of ovary [16] (Fig. 7.1).

Yamada et al. [20] proposed three major processes by which iron induces oxidative stress in endometriosis leading to EAOC (Fig. 7.1).

SRAP (Steroid Receptor Activator Protein) is a protein that enhances estrogen receptor-beta expression. The activation of estrogen receptor-beta increases endometrial cellular apoptosis, because it augments pro-apoptotic gene expression. Methylation of DNA suppresses pro-apoptotic gene activity by altering the chromatin structure and plays a role in the pathogenesis of ovarian cancer. Lin et al. observed decreasing levels of estrogen receptor beta expression when endometriosis of the ovary progress to atypical endometriosis, which then leads to ovarian clear cell carcinoma [15, 21] (Fig. 7.2). Previous studies have reported decreased levels of ER-beta m-RNA expression in estrogen dependent tumors like breast, ovarian and prostate cancers which highlights on the evidence that loss of ER-beta expression may be involved in carcinogenesis [21]. Lin k et al. [15], in their study speculated that during the malignant transformation of endometriosis to clear cell carcinoma, SRAP (Steroid Receptor Activator Protein) acts as a co-repressor, hypermethylates the promoter region of ER-beta (Estrogen Receptor-beta), suppressing gene activity and contributing to clear cell carcinoma of the ovary.

Estrogen receptor-beta is a tumor suppressor gene and therefore reduces the growth of tumor cells. It reduces the expression of genes involved in the cell cycle such as cyclin D. It decreases the proportion of cells in the S phase of the cell cycle, which is the synthesis phase where the replication of DNA occurs. However, Estrogen receptor beta increases the proportion of cells in the G2-M Phase, which is the cell cycle check point where DNA damage is assessed before the cell enters the mitotic phase. ER-β indirectly acts on ER-α and hence, inhibits cell proliferation. Whenever there is a decrease in ER-β expression, there is reversal of all these mechanisms and cell proliferation increases, leading to carcinoma [22] (Figs. 7.3, 7.4 and 7.5).

Endometriosis and endometrioid ovarian carcinoma cells are estrogen dependent and predominantly positive for estrogen receptor beta unlike clear cell carcinoma, which has low ER expression. Endometriotic stromal cells have higher levels of ER-beta expression due to deficient methylation. These increased ER-beta levels increase cyclooxygenase 2 [cox-2] and decrease progesterone receptor (PR) and ER alpha. Interaction with the estrogen receptor enhances the transcription of genes and promotes the synthesis of specific RNAs and proteins. Increased COX-2 levels are linked to endometriosis and also early malignant transformation (Fig. 7.5).

Although endometriosis increases the risk of ovarian cancer, the long-term risk can be reduced by hysterectomy without oophorectomy, oral contraceptives, aspirin and breast feeding [23]. All of these preventive measures suppress ovulation, which increases inflammation in the pelvic region [23]. Consequently, it has been shown that persistent inflammation leads to an increased risk of cancer.

In particular, oral contraceptives are extremely effective because they counteract the pituitary gonadotropin hypothesis. The pituitary gonadotropin hypothesis states that the continuous presence of elevated luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels in ovarian cysts stimulate trapped epithelial cells, cause inflammation and play a primary role in the malignant transformation of such tissue to ovarian cancer [23]. Thus, oral contraceptives keep LH and FSH levels low through the negative feedback system involving the secretion of estrogen. If estrogen levels are high, as induced by oral contraceptives, then the hypothalamus, and, consequently, the pituitary gland, will secrete less LH and FSH, cutting off the gonadotropin supply necessary for epithelial cells trapped in ovarian cysts to grow. The best choice of oral contraception is one that combines both estrogen and progestin. This would suppress levels of both gonadotropins and eliminate the risk factors associated with unopposed estrogen [23].

Progesterone has been shown to counteract some of the biological effects of estrogen and increase endometrial cell apoptosis, thus making it preferable to estrogen-based medications. Oral contraceptives, of course, are not a viable treatment option for women who wish to become pregnant. In that case, other options must be explored. Nonetheless, oral contraception is a non-invasive treatment that may bring relief and reduce the risk of cancer in many women afflicted with endometriosis. A patient’s risk for developing ovarian cancer is significantly reduced after hysterectomy without oophorectomy. One reason may be that the procedure removes the pathway connecting the lower and upper genital tract, preventing inflammants from reaching the ovaries [23]. Thus, removing the constant inflammation lowers the risk of ovarian cancer because the immune system is not activated, which prevents the tissues from entering an OS state, which in turn prevents the tissue from entering an OS state and causing DNA damage. However, unlike the treatment proposed with oral contraceptives, a hysterectomy is not an option for many women, including those of reproductive age who wish to preserve their fertility. Additionally, hysterectomy is an invasive and complicated medical procedure that carries a risk of infection and surgical and post-operative complications. Thus, a hysterectomy is a much more radical form of treatment as opposed to an oral contraceptive, and it therefore should only be considered in severe cases.

Another viable option for reducing the risk of ovarian cancer in women with endometriosis is treatment with non-steroidal anti-inflammatory drugs (NSAIDS) [24]. Because these drugs are anti-inflammatory, they have a dual advantage for patients—they not only help reduce the primary inflammation in the pelvic region initially caused by the endometriosis, but they also may prevent the carcinogenesis of epithelial tumors by inhibiting cyclooxygenase-2, which inhibits the aromatase enzyme, reducing estrogen levels [24]. Therefore, NSAID therapy is a realistic treatment option for endometriosis patients. It is a simple and low-cost treatment that can be taken daily. Similarly, NSAIDs appear to have beneficial effects on both inflammation and ovarian cancer. It is important to note that this treatment option does not suppress ovulation, making it an acceptable option for women of reproductive age.