The pathogenic hypothesis supported by the most robust evidence is based on the so-called retrograde menstruation phenomenon. Viable endometrial fragments are driven through the fallopian tubes, possibly by a pressure gradient originating from dyssynergic uterine contractions. Once they reach the peritoneal cavity, they can implant, grow and invade onto pelvic structures. The likelihood of this event is influenced epidemiologically by any menstrual, reproductive or personal factor that would augment pelvic contamination by regurgitated endometrium, such as early age at menarche or a long duration of menstrual flows, and biologically by any alteration at the molecular level that favors the stepwise process of cell implantation and growth at ectopic locations.
Further support for this etiology is derived from studies of obstructed or compromised outflow tracts. In adolescent girls with congenital outflow obstruction, the prevalence of endometriosis is high. Likewise, iatrogenic obstruction of the outflow tract in a non-human primate model results in endometriotic lesions within the peritoneal cavity. Even subtle compromise of antegrade menstruation may predispose to endometriosis, as evidenced by the higher prevalence of endometriosis in women with a uterine septum and cervical stenosis . The anatomic distribution of endometriotic lesions also favors the retrograde menstruation theory. Superficial implants are more often located in the posterior compartment of the pelvis and in the left hemipelvis. The propensity for lesions to implant in the posterior cul de sac is explained by the accumulation of regurgitated menstrual effluent in this most dependent portion of the peritoneal cavity under the influence of gravity. In allowing flow from the anterior to posterior compartment in the upright or supine position, a retroverted uterine position is correlated with the finding of endometriosis. By acting as an obstacle to the diffusion of menstrual effluent from the left fallopian tube, the sigmoid colon promotes stasis of this effluent, thereby extending the interval for refluxed endometrial fragments to implant in the left hemipelvis.
Among theories proposing a non-uterine origin of disease, coelomic metaplasia involves the transformation of normal peritoneal tissue to ectopic endometrial tissue. Agents responsible for such transformation remain poorly defined, although EDCs may be candidates. The closely related induction theory holds that an endogenous inductive stimulus, such as a hormonal or immunologic factor, promotes the differentiation of cells in the peritoneal lining to endometrial cells. Finally, the theory of embryonic Mullerian rests, or mullerianosis, purports cells residual from embryologic Mullerian duct migration maintain the capacity to develop into endometriotic lesions under the influence of estrogen beginning at puberty or perhaps in response to estrogen mimetics. These theories find support in epidemiologic studies reporting a twofold increased risk of endometriosis in women exposed to diethylstilbestrol in utero.
A more recent proposal suggests extra-uterine stem/progenitor cells originating from bone marrow may differentiate into endometriotic tissue. Candidate cell lineages include bone marrow mesenchymal stem progenitors and endothelial progenitors, and this represents an active area of investigation. Support for theories advocating a non-endometrial origin for endometriosis is derived from clinical accounts of histologically confirmed endometriotic tissue in patients without menstrual endometrium, such as individuals with Rokitansky-Kuster-Hauser syndrome and men with prostate cancer undergoing high dose estrogen treatment.
The theory of benign metastasis holds that ectopic endometrial implants are the result of lymphatic or hematogenous dissemination of endometrial cells. Microvascular studies demonstrated flow of lymph from the uterine body into the ovary, rendering possible a role for the lymphatic system in the etiology of ovarian endometriosis. Endometriosis within lymph nodes has been documented in a baboon model of induced endometriosis, and in 6-7% of women at lymphadenectomy. The strongest evidence for the theory of benign metastasis is derived from reports of histologically proven endometriotic lesions occurring in sites distant from the uterus to include bone, lung and brain.