Deeply infiltrative endometriosis, with a depth of at least 5 mm beneath the peritoneum, can present as nodules in the cul-de-sac, rectosigmoid, and bladder area and occurs with other forms of peritoneal or ovarian endometriosis (52). According to anatomic, surgical, and pathologic findings, deep endometriotic lesions originate intraperitoneally rather than extraperitoneally. The lateral asymmetry in the occurrence of ureteral endometriosis is compatible with the menstrual reﬂux theory and with the anatomic differences of the left and right hemipelvis (37). Adolescents and young women can have peritoneal disease (53). This observation, together with evidence from the development and spontaneous evolution of endometriosis in baboons, supports the notion that endometriosis starts as peritoneal disease and that the three different phenotypes and locations of endometriosis (peritoneal, ovarian, and deep) represent a homogenous disease continuum with a single origin (i.e., regurgitated endometrium), rather than three different disease entities, as advocated by some investigators (37,54,55).
Extrapelvic endometriosis, although rare (1% to 2%), may result from vascular or lymphatic dissemination of endometrial cells to many gynecologic (vulva, vagina, cervix) and nongynecologic sites. The latter include bowel (appendix, rectum, sigmoid colon, small intestine, hernia sacs), lungs and pleural cavity, skin (episiotomy or other surgical scars, inguinal region, extremities, umbilicus), lymph glands, nerves, and brain (56).
Coelomic Metaplasia The transformation (metaplasia) of coelomic epithelium into endometrial tissue is a proposed mechanism for the origin of endometriosis. One study evaluating structural and cell surface antigen expression in the rete ovarii and epoophoron reported little commonality between endometriosis and ovarian surface epithelium, suggesting that serosal metaplasia is unlikely in the ovary (57). The results of another study involving the genetic induction of endometriosis in mice suggest that ovarian endometriotic lesions may arise directly from the ovarian surface epithelium through a metaplastic differentiation process induced by activation of an oncogenic K-ras allele (50).
Induction Theory The induction theory is an extension of the coelomic metaplasia theory. It proposes that an endogenous (undefined) biochemical factor can induce undifferentiated peritoneal cells to develop into endometrial tissue. This theory is supported by experiments in rabbits but is not substantiated in women or nonhuman primates (58,59).
Genetic Factors Increasing evidence suggests that endometriosis is partially a genetic disease. Recent findings that support this association include evidence of familial clustering in humans and in Rhesus monkeys, a founder effect detected in the Icelandic population, concordance in monozygotic twins, a similar age at onset of symptoms in affected nontwin sisters, a six-to nine-times increased prevalence of endometriosis among first-degree relatives of women compared with the general population, and a 15% prevalence of magnetic resonance imaging (MRI) findings suggestive of endometriosis in the first-degree relatives of women with stage III or IV disease based on the classification of the American Society of Reproductive Medicine (60). The induction of humanlike endometriosis by genetic activation of an oncogenic K-ras allele lends further support to the genetic basis of this disorder (50).