Biology and Pathophysiology
Endometriosis is characterized by the presence of endometrial tissue in parts of the body where it should not normally be present. The pelvic peritoneum (membrane that covers the organs within the pelvis), ovaries, and rectovaginal septum (area between the rectum and vagina) are the most susceptible (Burney 2012; Bulun 2009). As of the time of this writing, there is no single unifying theory as to the genesis of endometriosis; although several have been proposed (Burney 2012; Connolly 2009).
One predominant theory is that endometriosis occurs via a process known as “retrograde menstruation” (Burney 2012; Schenken 2013). This theory suggests that endometrial tissue leaks into the peritoneal cavity during menstruation, allowing endometrial tissue to implant into other sites in the pelvis (Burney 2012). Women with congenital anatomical abnormalities that impair the flow of menses from the uterus into the vagina have an increased risk of endometriosis, further supporting this theory (Olive 1987). However, retrograde menstruation occurs in up to 90% of menstruating women and not all of these women develop endometriosis, suggesting other factors may also be important (Burney 2012; Schenken 2013; Connolly 2009).
Another theory on the development of endometriosis is called the “coelomic metaplasia” theory. This theory suggests that endometriosis occurs when cells lining the coelom, the cavity between the body wall and intestines, change their cell type to form endometrial tissue. Cells of the endometrium and coelom arise from the same cell type during embryonic development, and their differentiation is under the control of hormones, primarily estrogen (Signorile 2010; Rizner 2009; Schenken 2013; Matsuura 1999). This theory is supported by a case report of endometriosis in a woman without a uterus due to a genetic defect (ie, Mayer-Rokitansky-Küster-Hauser syndrome), suggesting retrograde menstruation could not have been the cause of her condition (Mok-Lin 2010).
Blood and Lymphatic Dissemination
Other researchers hypothesize that viable endometrial cells may travel from the endometrium through lymphatic or blood circulation. Eventually, these cells may implant at other sites and grow, giving rise to endometriosis in a manner similar to the metastasis of tumor cells. There are many aspects of this theory that still need to be conclusively studied (Tempfer 2011; Burkle 2013; Elsevier 2011).
Inflammation may also play an important role in endometriosis (Ziegler 2010; Reis 2013). Endometriotic tissue produces excess inflammatory mediators such as prostaglandin E2 and prostaglandin F2α (Bulun 2009; Ziegler 2010; Reis 2013). In addition to helping ectopic endometrial tissue implants grow in other parts of the body, inflammation may also play an important role in the pain caused by endometriosis (Reis 2013; Bulun 2009). Endometrial tissue in areas outside the uterus can trigger an immune response that causes the release of large amounts of inflammatory cytokines (Bruner-Tran 2013; Reis 2013). These cytokines may increase the activity of immune cells, such as mast cells, which can affect nearby nerves and contribute to pain (Anaf 2006). In addition to increased overall inflammation, women with endometriosis may have defects in their immune systems that make it easier for endometrial tissue to grow and survive (Schenken 2013; Ziegler 2010).
Hormonal imbalance may contribute to endometriosis as well. During a woman’s menstrual cycle, endometrial tissue grows and then regresses (Reis 2013; Krikun 2012). Estrogen is responsible for the proliferation of the endometrial lining (Bulun 2006; Burney 2007). The growth and progression of endometriosis is also dependent on estrogen and can be treated by suppressing estrogen levels (Kitawaki 2002; Bulun 2006). Conversely, progesterone can help stop the growth of normal and ectopic endometrial tissue. However, tissue from endometriosis is notably more resistant to progesterone’s anti-growth effects (Zeitoun 1998; Reis 2013; Bulun 2006). This idea is supported by genetic studies of endometriotic tissue samples that have shown reduced activity of an enzyme called 17β-hydroxysteroid dehydrogenase type-2 (17β-HSD2), which is needed to metabolize (and inactivate) estrogen (Zeitoun 1998). Normally, this enzyme is expressed in response to the hormone progesterone. However, in “resistant” endometriotic tissue, progesterone does not trigger the expression of 17β-HSD2 and subsequent metabolism of estrogen (Reis 2013; Zeitoun 1998; Bulun 2006).
Genetic mutations that cause abnormal cell growth also promote endometriosis (Burney 2012; Reis 2013). Inherited genetic alterations may account for the increased risk of endometriosis in women with a first-degree relative (mother or sibling) with endometriosis (Burney 2012; Simpson 1980; Schenken 2013).