Pathogenesis

Several theories have been proposed to explain the histogenesis of endometriosis.

The implantation theory proposes that endometrial tissue desquamated during menstruation passes through the fallopian tubes, where it gains access to and implants on pelvic structures. The incidence of retrograde menstruation is similar in women with and without endometriosis. Thus, the development of endometriosis could depend on the quantity of endometrial tissue reaching the peritoneal cavity, specific factors enhancing attachment of endometrial cells to the peritoneum and ovary, or the capacity of a woman's immune system to remove the refluxed menstrual debris.

The direct transplantation theory is the probable explanation for endometriosis that develops in episiotomy, cesarean section, and other scars following surgery. Endometriosis in locations outside the pelvis likely develops from dissemination of endometrial cells or tissue through lymphatic channels or blood vessels.

The coelomic metaplasia theory proposes that the coelomic (peritoneal) cavity contains undifferentiated cells or cells capable of dedifferentiating into endometrial tissue.

This theory is based on embryologic studies demonstrating that all pelvic organs, including the endometrium, are derived from the cells lining the coelomic cavity. The induction theory, an extension of the coelomic metaplasia theory, postulates that the refluxed endometrial debris releases a product that activates undifferentiated peritoneal cells to undergo metaplasia. There is no conclusive proof that peritoneum can undergo spontaneous or induced metaplasia.

Anatomic alternations of the pelvis that increase tubal reflux of menstrual endometrium increase a woman's chance of developing endometriosis. The incidence of endometriosis is increased in young women with genital tract obstructions that prevent expulsion of menses into the vagina and increase the likelihood of tubal reflux.

Other studies have suggested that deficient cellular immunity results in an inability to recognize the presence of endometrial tissue in abnormal locations. Decreased natural killer cell activity resulting in decreased cytotoxicity to autologous endometrium has been reported in women with endometriosis. The presence of increased concentrations of leukocytes and their cytokine products in peritoneal fluid of women with endometriosis may play a role in the initiation and growth of the ectopic implants. The immune system clearly has an important, albeit unclear, role in the pathogenesis of endometriosis.

The possibility of a familial tendency for endometriosis has been recognized for several decades. If a patient has endometriosis, a first-degree female relative has a 7% likelihood of being affected similarly.

The risk or endometriosis is 7 times greater if a first-degree relative has been affected by endometriosis. Because no specific mendelian inheritance pattern has been identified, multifactorial inheritance has been postulated. A relative risk for endometriosis of 7. 2 has been found in mothers and sisters, and a 75% (6 of 8) incidence has been noted in homozygotic twins of patients with endometriosis. In another twin study, 51% of the variance of the latent liability to endometriosis may be attributable to additive genetic influences. Other investigators reported that 14 monozygotic twin pairs were concordant for endometriosis, and 2 pairs were discordant. Of these twin pairs, 9 had moderate to severe endometriosis.

A relationship has been shown between endometriosis and systematic lupus erythematosus, dysplastic nevi, and a history of melanoma in women of reproductive age. Endometriosis also is linked to the presence of individual human leukocyte antigens.

Mutations

In women with endometriosis, no mutations were found in the TP53 and RASK genes. No significant differences were observed in N314D (galactose-1-phosphate uridyl transferase) mutation frequency between women with endometriosis (18%) and controls (17%).

Steroid Receptor Genetics

An association of estrogen receptor gene polymorphisms (two-allele and multiallele polymorphism) with endometriosis has been reported. Furthermore, various exon-deleted progesterone-receptor messenger RNAs (mRNAs) have been documented in human endometrium and ovarian endometriosis.

Aneuploidy

Epithelial cells of endometriotic cysts are monoclonal on the basis of phosphoglycerate kinase gene methylation, but normal endometrial glands are monoclonal. In a comparison of endometriotic tissue with normal tissue from the endometrium flow, cytometric DNA analysis failed to show aneuploidy. However, more recent studies using comparative genomic hybridization or multicolor in situ hybridization showed aneuploidy for chromosomes 11, 16, and 17, increased heterogeneity of chromosome 17 aneuploidy, and losses of 1p and 22q (50%), 5p (33%), 6q (27%), 70 (22%), 9q (22%), and 16 (22%) of 18 selected endometriotic tissues.

Loss of Heterozygosity

Microsatellite DNA assays reveal an allelic imbalance (loss of heterozygosity) in p16 (Ink4), GALT, p53, and APOA2 loci in patients with endometriosis, even in stage II of endometriosis. Another report found in 28% of endometriotic lesions a loss of heterozygosity at one or more sites: chromosomes 9p (18%), 11q (18%), and 22q (15%).

Immunologic Factors and Inflammation

Although retrograde menstruation appears to be a common event in women, not all women who have retrograde menstruation develop endometriosis. The immune system may be altered in women with endometriosis, and it has been hypothesized that the disease may develop as a result of reduced immunologic clearance of viable endometrial cells from the pelvic cavity. Endometriosis can be caused by decreased clearance of peritoneal fluid endometrial cells due to reduced natural killer (NK) cell activity, or decreased macrophage activity. Decreased cell-mediated cytotoxicity toward autologous endometrial cells has been associated with endometriosis. However, these studies used techniques that have considerable variability in target cells and methods. Whether NK cell activity is lower in patients who have endometriosis than in those without endometriosis is controversial. Some reports demonstrate reduced NK activity, whereas others have found no increase in NK activity, even in women with moderate to severe disease. There also is great variability in NK cell activity among normal individuals that may be related to variables such as smoking, drug use, and exercise.

In contrast, endometriosis can also be considered a condition of immunologic tolerance, as opposed to ectopic endometrium, which essentially is self-tissue. It can be questioned why viable endometrial cells in the peritoneal fluid would be a target for NK cells or macrophages. Autotransplantation of blood vessels, muscles, skin grafts, and other tissues is known to be extremely successful in. Furthermore, there is no in vitro evidence that peritoneal fluid macrophages actually attack and perform phagocytosis of viable peritoneal fluid endometrial cells. High-dose immunosuppression can slightly increase the progression of spontaneous endometriosis in baboons. There is no clinical evidence, however, that the prevalence of endometriosis is increased in immunosuppressed patients.

The fact that women with kidney transplants, who undergo chronic immunosuppression, are not known to have increased infertility problems can be considered indirect evidence that these patients do not develop extensive endometriosis.

Substantial evidence suggests that endometriosis is associated with a state of subclinical peritoneal inflammation, marked by an increased peritoneal fluid volume, increased peritoneal fluid white blood cell concentration (especially macrophages with increased activation status), and increased inflammatory cytokines, growth factors, and angiogenesis-promoting substances. It has been reported in baboons that subclinical peritoneal inflammation occurs both during menstruation and after intrapelvic injection of endometrium. A higher basal activation status of peritoneal macrophages in women with endometriosis may impair fertility by reducing sperm motility, increasing sperm phagocytosis, or interfering with fertilization, possibly by increased secretion of cytokines such as tumor necrosis factor-a (TNF-a). TNF also may facilitate the pelvic implantation of ectopic endometrium. The adherence of human endometrial stromal cells to mesothelial cells in vitro has been increased by the pretreatment of mesothelial cells with physiologic doses of TNF-a. Macrophages or other cells may promote the growth of endometrial cells by secretion of growth and angiogenetic factors such as epidermal growth factor (EGF), macrophage-derived growth factor (MDGF), fibronectin, and adhesion molecules such as integrins. After attachment of endometrial cells to the peritoneum, subsequent invasion and growth appears to be regulated by matrix metalloproteinases (MMPs) and their tissue inhibitors.

There is increasing evidence that local inflammation and secretion of prostaglandins (PG) is related to differences in endometrial aromatase activity between women with and without endometriosis. Expression of aromatase cytochrome P450 protein and mRNA was observed in human endometriotic implants but not in normal endometrium, suggesting that ectopic endometrium produces estrogens, which may be involved in the tissue growth interacting with the estrogen receptor.

Inactivation of 17b-estradiol has been reported to be impaired in endometriotic tissues because of deficient expression of 17b-hydroxysteroid dehydrogenase type 2, which is normally expressed in eutopic endometrium in response to progesterone. Finally, the inappropriate aromatase expression in endometriosis lesions can be stimulated by prostaglandin E2 (PGE2). This also leads to local production of E2, which also stimulates PGE2 production, resulting in a positive-feedback system between local inflammation and estrogen-driven local growth of ectopic endometrium.

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