Endometriosis

Causation Prevalence Natural history Symptoms Diagnosis and classification Pathophysiology Conclusion

Endometriosis may be defined as the presence of functioning endometrial glands and stroma outside their usual location lining the uterine cavity. It has been identified in virtually all tissues and organs of the female body with the exception of the spleen, which seems to enjoy immunity to this disease process.

Endometriosis Causation

The development of endometriosis, no matter where the location, is probably a multifactorial event. Many theories relating to the aetiology of endometriosis have been proposed. These hypotheses have been divided into four groups: transport, coelomic metaplasia, embryonic cell rests, and numerous immunological theories. The most widely accepted transportation theory suggests that viable endometrial cells reflux through the fallopian tubes during menstruation and implant and grow on the surrounding pelvic structures and peritoneum. This theory is lent support by data showing an increased occurrence of endometriosis in women with Mullerian duct anomalies resulting in an obstructed genital outflow tract and thus increased retrograde menstruation. Added to this are epidemiological data suggesting that women who menstruate more frequency, more heavily, or for a longer duration of time, and therefore have increased exposure to retrograde menstruation, also have a higher risk of developing the disease.

These data suggest that any exposure of the pelvic and abdominal peritoneum to menstrual reflux would result in an increased risk of endometriosis. Unfortunately, this single cause and effect relation is weakened by several factors, such as the observation that 90% of women with patent fallopian tubes have bloody peritoneal fluid if they are laparoscoped during the perimenstrual period, yet the prevalence of endometriosis in reproductive age women is reported by one investigator to be only 2.5%. Other transport theories include dissemination of endometrial fragments through lymphatics and blood vessels and inadvertent iatrogenic dissemination during abdominal or pelvic surgery. Lymphatic and haematogenous dissemination does provide an attractive explanation for the occurrence of endometriosis at locations outside the abdominal cavity. Vascular metastasis of endometrial fragments has been observed; and a necropsy study evaluating a group of patients with pelvic endometriosis showed that 29% had pelvic lymph-nodes containing endometrial-like glands or stroma, or both.

The coelomic metaplasia hypothesis states that peritoneal mesothelium undergoes metaplasia, forming typical endometrial-like glands and stroma. This theory would explain endometriosis in women with Mullerian agenesis, who have an absent uterus or a hypoplastic non-functioning uterus, or the occasional presence of endometriosis in men. The embryonic cell rests theory is that the developing Mullerian duct system may leave behind small clusters or rests of Mullerian cells that have the potential to develop into functioning endometrial-like tissue. Since no cell rests of this type have been documented, however, this proposal remains only speculative.

The possibility that the development and progression of endometriosis is associated with abnormal immune function is the most recent hypodhesis for the aetiology of this disease process. Over the past 10-15 years, various data have suggested alterations in both cell-mediated and hormonal immunity in women with endometriosis. Whether this immunological factor is a separate cause or a synergistic factor to one or more of the other causes is yet to be established. There is, however, little doubt that the immunological process does play a part in the development and progression of endometriosis.

Evidence for this relation comes from investigations in both animals and man. In two unrelated studies in which the immune system was suppressed in rhesus monkeys, by proton radiation and by polychlorinated biphenyls, endometriosis developed more frequently clan in controls. Numerous workers have also identified changes in one or more factors of the immune system in women with this disease process. An early study by Weed and Arguembourg identified the presence of C3 component of complement and IgG deposits in uterine endometrium of women with endometriosis, suggesting that in some way ectopic endometrium was related to an alteration of the immune process which was manifested by an immune reaction to normal endometrium. At roughly the same time, Mathur et al identified IgG and IgA autoantibodies against ovarian and endometrial tissue in serum and in vaginal and cervical secretions of women with endometriosis. Unfortunately, some of these studies were not confirmed by other groups. Switchenko et al were unable to show an association between increased anti-endometrial antibodies and endometriosis.

Halme and Zeller and their colleagues identified large numbers of activated macrophages in women with endometriosis, indicating that the endometriotic process was directly related to an immunological peritoneal reaction. It is noteworthy that these peritoneal macrophages from such women produce substantially more fibronectin, a growth factor for fibroblasts, than do macrophages from healthy women.

Other evidence of peritoneal fluid from altered immunity includes work showing decreased cytotoxicity to endometrial cells attributable to a defect in natural killer cells. This response may in part be due to an increased resistance to lysis by the endometrial cells.

These data taken together suggest that women with endometriosis have endometrial cells that are somewhat less sensitive to the normal body defence mechanisms and, as a result, implant and grow more easily in ectopic sites. Furthermore, the accompanying altered immune response acts inappropriately with the production of increased tissue growth factors such as fibronectin stimulating a fibrotic reaction that protects the endometriotic implants.

Endometriosis Prevalence

The prevalence of endometriosis in reproductive-aged women in world-wide publications is reported to be within the range 1-50%. Jeffcoate reported that endometriosis was found in 10-25% of women undergoing laparotomy by gynaecologists in the UK and the USA.

Of 459 consecutive patients with primary infertility investigated at the Johns Hopkins Hospital, 114 (25%) proved to have endometriosis. Verkauf prospectively identified endometriosis in 38.5% of infertile women and 5.2% of fertile women. Other workers have confirmed that infertile women are 7-10 times more likely to have endometriosis than their fertile counterparts. Selection bias--ie, the selection of patients for which a particular type of operation was done--probably accounts for the wide variation in the reported prevalence.

Endometriosis Natural history

The natural history of endometriosis is not clearly understood. The disease seems to progress in most untreated women, although spontaneous regression has been described in mild cases. Surgical and medical therapies might prevent a temporal progression. What is the effect of pregnancy on the clinical course of endometriosis? Although pregnancy is thought to induce involution of endometriotic implants, McArthur and Ulfelder showed that the behaviour of endometriosis during the gravid state was highly variable, and regression of disease seemed to be due to decreased tissue responsiveness to hormonal stimulation rather than necrosis of lesions.

Endometriosis Symptoms

Dysmenorrhea, dyspareunia, and pelvic, back, and rectal pain are the more common symptoms described by women with endometriosis. These symptoms have been assumed to be caused by endometriotic implants; however, the development of such symptoms cannot be regarded as diagnostic of the disease state. The presence of laparoscopically diagnosed endometriosis in patients with chronic pelvic pain ranges from 4% to 52% in published series.

Although deep infiltration of endometriosis into fibromuscular tissue of the pelvis has been strongly correlated with pelvic pain, there is no universally accepted hypothesis that explains how endometriosis can cause the other common symptoms. Infertility is also commonly associated.

Endometriosis Diagnosis and classification

Endometriosis is suspected from the clinical history, and the diagnosis is confirmed by imaging techniques including ultrasonography, computed tomography, and magnetic resonance imaging. However, a true diagnosis can be made only by direct observation and biopsy showing typical glands or stroma or both. Although classic blue-black peritoneal implants of endometriosis are generally easily recognised, active disease hidden beneath fibrosis or nonclassic disease consisting of white, red, or brown lesions requires histological confirmation.

Donnez and co-workers further elucidated the biological characteristics of peritoneal endometriosis. With an advanced stereographic computer technology for the investigation of three-dimensional architectures of peritoneal endometriosis, they identified two distinct main types according to the presence or absence of ramifications. The apparently multifocal occurrence in two dimensions of glandular epithelium was not confirmed by three dimensional studies showing that all epithelial glands were interconnected by luminal structures in each peritoneal lesion. Stoval a al using immunohistochemical techniques were able to detect type 1, type 3, and type 4 collagen in endometrial implants. The distribution of collagen in ectopic endometrial implants was similar to that in intrauterine endometrium from patients without endometriosis. Type 1 collagen was the predominant collagenous tissue associated with deep ectopic endometrial implants.

Attempts to classify endometriosis date back to 1949 and since the initial description over a dozen different classification systems have been proposed, the most recent of which has been the 1985 American Fertility Society revised classification. The fact that even this is now being considered for further revision suggests that the perfect classification is yet to be developed. A recent classification should certainly be used in preference to an old one.

Endometriosis Pathophysiology

Of the troubles afflicting patients with endometriosis, pelvic pain and infertility are by far the most important. Pelvic pain probably has several origins. Of most consequence seems to be deep infiltration of endometriosis into pelvic fibromuscular tissue; however, the adhesions to uterus, adnexae, bowel, and omentum undoubtedly have an important role.

The relation between endometriosis and infertility is less well understood and is felt to relate to multiple factors, including altered tubal function, folliculogenesis, peritoneal environment, and an altered immunological system that is suppressive to gametes and to fertilisation and embryo implantation.

Endometriotic implants within the fallopian tube or ovary may promote a local inflammatory response that directly harms tubal function and prevents pick-up of normal oocytes. Defective folliculogenesis seems important in reduced fertility. Reduced follicular growth, assessed by follicular diameter change, has been correlated with endometriosis. Other data have also shown smaller follicles as well as lower preovulatory oestradiol values. Additionally, luteinised unruptured follicle syndrome has been reported to arise more commonly in patients with endometriosis. Oestradiol and progesterone concentrations in blood from peripheral and ovarian veins of women with endometriosis during early follicular phase accord with these data and have suggested an increased frequency of inadequate luteolysis and prolongation of corpus luteum function into the subsequent menstrual cycle.

What is the effect on fertilisation and preimplantation embryo development? Earlier adverse reports have been proved foundless by more recent reports of fertile women and patients with untreated endometriosis as control groups, which showed no relation between endometriosis and an increased rate of early pregnancy wastage.

Changes in the nature and constituents of peritoneal fluid have attracted considerable attention. Halme et al demonstrated increased activation of pelvic macrophages in infertile women with endometriosis, and Chacho et al noted not only increased peritoneal fluid and numbers of macrophages and activated macrophages, but also a pronounced decrease in the percentage of ova penetrated in a zone-free hamster egg spermatozoa penetration assay when these macrophages were added to the assay medium. Increases in leucocytes, macrophages, helper T-cells, lymphocytes, and natural killer cells have been seen in women with stage I and stage II endometriosis Additionally, peritoneal macrophages from patients with stage I and II endometriosis have proved substantially more cytotoxic than those from healthy women. Other cytotoxic factors have also been noted.

Finally, prostaglandins, interleukins, and other substances produced by macrophages may be harmful to reproduction in various ways. High peritoneal-fluid prostaglandins have been related to ovulation interference as well as an increase in tubal motility, so that the embryo arrives in the uterine cavity at a suboptimum time for implantation. Fakih et al demonstrated the presence of interleukin-1 in peritoneal fluid of women with endometriosis. Interleukin-1 adversely affects mouse embryo growth as well as stimulate fibroblast proliferation, collagen deposition, and fibrin formation. These data collectively suggest that changes in peritoneal environment do play an important part in the interruption of the process of normal folliculogenesis, ovulation, conception, and possible implantation.

Endometriosis Conclusion

The most important advances in the study of endometriosis relate not to cause and progression of the disease but to abnormalities in immunity and the peritoneal environment that result from the disease. Much is yet to be accomplished before investigators understand how endometriosis relates to the common complaints of pelvic pain and reproductive failure.

Last updated Jan 4/07