Etiology

Several theories have been proposed to explain the underlying mechanisms that allow for the development and progression of endometriosis, yet no single one holds true for every woman or manifestation.

  • Retrograde menstruation: represents a portal for endometrial tissue to gain exposure to peritoneal surfaces.[19] Although logical, this concept fails to explain the low rate of disease compared with such a common event (90% of menstruating women will manifest retrograde flow).[20]

  • Deficient cell-mediated immune response: reduced scavenger receptivity by activated, nonadherent macrophages (first-line response to foreign body) is present in women with endometriosis and may represent an ineffective mechanism for clearing menstrual effluent.[21]

  • Mullerian rests: differentiation of coelomic epithelium into endometrial glands is a possible mechanism. Endometriosis documented in premenarcheal girls is thought to arise from mullerian rests, cells of paramesonephric origin already in the pelvis, which are stimulated by estrogen production once maturation of the hypothalamic-pituitary-ovarian axis occurs.[22] Deep peritoneal disease with no obvious superficial implants is suggestive of this process, and may explain advanced stages noted in particularly young cohorts.

  • Vascular and lymphatic dissemination: suggested by presence of endometriosis pulmonary disease.

  • Increased levels of various inflammatory and angiogenic mediators have been consistently documented in peritoneal fluid of women with endometriosis.[23][24] Products of oxidative stress further contribute to the inflammatory reaction by formation of free radicals and through lower levels of protective antioxidants.[25]

  • Post-pubertal girls with mullerian anomalies that obstruct flow of menstrual blood are also at risk for developing endometriosis.[26] This includes transverse vaginal septum, uterine didelphys (double uterus) with obstructed hemivagina, and imperforate hymen (not mullerian).

  • An increased prevalence of autoimmune diseases has been noted in women with surgically confirmed endometriosis.[27]

  • Genetic predisposition to disease has been well documented in sibling pair studies.​[9][28]​​

  • The composite theory asserts that the underlying mechanism of endometriosis includes both vascular/lymphatic dissemination and the differentiation of coelomic epithelium into endometrial glands.

Pathophysiology

Whereas the association between severe endometriosis and subfertility appears logical (distorted anatomy, significant involvement of the tube and/or ovary due to scarring or prostaglandin overproduction that can interfere with fertilization or implantation), the mechanism for lesser stages is not so clear. It has been postulated that an altered immune response, hormonal influences and production of various cytokines and growth factors affect ovulation, oocyte transport within the tube and embryo implantation in the uterus.[4] None of these have been confirmed.

Pelvic pain is a common complaint for women with endometriosis, yet the degree of involvement noted at surgery does not always correlate with the severity of symptoms. Dysmenorrhea may be most common in early-stage disease since prostaglandin production may be higher within these implants. It has been suggested that chronic pain may be due to the resulting fibrosis that occurs with longstanding inflammation. The resulting deeply infiltrating disease and adhesions distort normal anatomy. What remains unclear is which etiological processes produce such aggressive features; for example, does early-stage progress to late-stage, or do mullerian rests invade deep into the pelvic floor from their initial starting point? Noxious stimuli (e.g., cytokines) can provoke pelvic floor nerves and musculature, which can also contribute to chronic symptoms. Furthermore, fibrotic disease and peritoneal disease, which are often associated with ovarian endometrioma, distort normal anatomy and represent the probable etiology of the pelvic pain.[9]​ In less common scenarios, patients may present with neuropathic pain due to nerve entrapment from endometriosis, often involving the sacral nerve roots or pudendal nerve. Even when endometriosis has been surgically documented, the physician should remain alert to other potential causes of chronic pain and not always assume a causal relationship. Women with endometriosis may demonstrate a heightened myofascial as well as central nervous system response when provoked, further contributing to the development of associated pain syndromes.[29][30]

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