**5.1 Etiology**

Despite extensive research, its pathogenesis still remains elusive and the disorder is considered to be 'enigmatic'. Endometriosis is a multi-factorial disease with multi-faceted features. The theories that have withstood the test of time and remain in vogue include retrograde menstruation, coelomic metaplasia, and endometrial stem cells. All the theories on its pathogenesis must be taken complementary to one another and by no way are mutually exclusive. The most widely accepted theory is the implantation of viable endometrial tissue onto peritoneal visceral structures from retrograde menstrual flow into the pelvic cavity (17). However, the origin is multifactorial, also having hormone, immune, and genetic components. The relationship of endometriosis to estrogen is well-

Endometriosis may develop anywhere within the pelvis and on other extrapelvic peritoneal surfaces. Although the condition is usually limited to the ovaries, uterosacral ligaments, and Douglas' pouch, it has been reported in almost every organ of the body. Extra-pelvic endometriosis refers to endometrial implants found elsewhere in the body, including the skin, central nervous system, gastrointestinal tract, urinary tract, lungs, and heart. Macroscopically, three forms of endometriosis are described: superficial peritoneal (or ovarian) endometriosis, endometriotic cyst of the ovary or ovarian endometrioma, and deep

The most commonly affected sites are the pelvic organs and peritoneum, although other parts of the body such as the lungs are occasionally affected. The extent of the disease varies from a few, small lesions on otherwise normal pelvic organs to large, ovarian endometriotic

There can be extensive fibrosis in structures such as the uterosacral ligaments and adhesion formation causing marked distortion of pelvic anatomy. Disease severity is assessed by simply describing the findings at surgery or quantitatively, using a classification system such as the one developed by the American Society for Reproductive Medicine (ASRM) (1997). There is no correlation between such systems and the type or severity of pain

Endometriosis typically appears as superficial "powder burn" or "gunshot" lesions on the ovaries,serosal surfaces and peritoneum-black, dark-brown, or bluish-puckered lesions, nodules or small cysts containing old haemorrhage surrounded by a variable extent of fibrosis. Atypical or "subtle" lesions are also common, including red implants (petechial, vesicular, polypoid, hemorrhagic, red flamelike) and serous or clear vesicles. Other appearances include white plaques or scarring and yellow-brown peritoneal discoloration of

Endometriomas usually contain thick fluid like tar; such cysts are often densely adherent to the peritoneum of the ovarian fossa and the surrounding fibrosis may involve the tubes and bowel. Deeply infiltrating endometriotic nodules extend more than 5mm beneath the peritoneum and may involve the utero-sacral ligaments, vagina, bowel, bladder or ureters.

Despite extensive research, its pathogenesis still remains elusive and the disorder is considered to be 'enigmatic'. Endometriosis is a multi-factorial disease with multi-faceted features. The theories that have withstood the test of time and remain in vogue include retrograde menstruation, coelomic metaplasia, and endometrial stem cells. All the theories on its pathogenesis must be taken complementary to one another and by no way are mutually exclusive. The most widely accepted theory is the implantation of viable endometrial tissue onto peritoneal visceral structures from retrograde menstrual flow into the pelvic cavity (17). However, the origin is multifactorial, also having hormone, immune, and genetic components. The relationship of endometriosis to estrogen is well-

The depth of infiltration is related to the type and severity of symptoms (4).

**4. Anatomic sites** 

cysts endometriomas).

symptoms (66).

the peritoneum (66, 67).

**5. Pathophysiology** 

**5.1 Etiology** 

infiltrating endometriosis (DIE).(4)

established. Two thirds of women with a diagnosis of endometriosis report having a family member with endometriosis. A large percentage of women with endometriosis have other co-morbidities such as fibromyalgia, chronic fatigue syndrome, hypothyroidism, allergies, asthma, and auto-immune disorders. The associated risk factors are directly related to low body mass index (BMI), and family history and are inversely related to exercise (18).

#### **5.2 Retrograde menstruation**

The earliest and most widely accepted theory relates to retrograde menstruation through the fallopian tubes with subsequent dissemination of endometrial tissue within the peritoneal cavity. Sampson's theory of endometrial implantation, offered in the 1927, proposes that retrograde menstruation through the fallopian tubes was responsible for endometriotic lesions. Three prerequisites are necessary for Sampson's theory: (1) retrograde menstruation, (2) viability of menstrual endometrial cells, and (3) implantation of endometrial cells onto the peritoneal/ovarian surfaces (3). Since the introduction of his theory, retrograde menstruation has been confirmed at laparoscopy, and it appears to occur in the vast majority of women. Keettel and Stein in the 1950s demonstrated the viability of shed menstrual endometrial cells by invitro culture of menstrual endometrium (19). The viability of retrograde menstrual endometrium has been shown by Mungyer et al by culturing endometrial glands and stroma collected from peritoneal lavage (20). In addition to these invitro studies, Ridley and Edwards injected menstrual blood into the skin of women scheduled for a laparotomy in the next 3 to 6 months. On excision of this tissue, several women had endometriotic lesions at the injection site. Further circumstantial evidence supporting Sampson's theory is the increased risk of endometriosis in women with Mullerian anomalies and other outflow tract obstructions (21).

Refluxed endometrial fragments adhere to and invade the peritoneal mesothelium and develop a blood supply, which leads to continued implant survival and growth. However, this theory fails to explain the presence of endometriosis in such remote areas outside the peritoneal cavity, as the lungs, skin, lymph nodes, and breasts. Moreover, the presence of the disease in early puberty and exceptionally also in newborns further contrasts the validity of the theory (22).

#### **5.3 Coelomic metaplasia**

The coelomic metaplasia theory claims that formation of endometriomas in the ovary or recto-vaginal endometriosis is caused by metaplasia of the coelomic epithelium, perhaps induced by environmental factors (23). Because the ovary and the progenitor of the endometrium, the müllerian ducts, are both derived from coelomic epithelium, metaplasia may explain the development of ovarian endometriosis. In addition, the theory has been extended to include the peritoneum because of the proliferative and differentiation potential of the peritoneal mesothelium.

This theory would explain why most women have some degree of retrograde menstruation but only a little percentage has endometriosis and the presence of the disease in absence of menses. However, the absence of endometriosis in other tissues derived from coelomic epithelium argues against this theory (22).

Endometriosis 9

and Androgen Receptors (AR) - these receptors must be and have shown to be intimately involved in the pathogenesis of endometriosis. ERs, PRs and AR, along with glucocorticoid receptor and mineralocorticoid receptor, form the steroid receptors (SRs) family, which is one of three members of the nuclear receptor (NR) superfamily of transcription factors. Besides the SR family, other members of the NR superfamily, such as vitamin D receptor, retinoic acid receptor, and peroxisome proliferator-activated receptor may also be involved

There is ample evidence indicating that alterations in both cell-mediated and humoral immunity contribute to the pathogenesis of endometriosis. Increased number and activation of peritoneal macrophages, decreased T cell and natural killer (NK) cell cytotoxicities are the alterations in cellular immunity, yielding diminished removal of ectopic endometrial cells from the peritoneal cavity. In addition, increased levels of several proinflammatory cytokines and growth factors produced by immune and endometrial cells are likely to be involved in facilitating implantation and growth of ectopic endometrial cells by promoting

There is evidence that TNF-α promotes the adherence of stromal cells to the mesothelium and stimulates proliferation of endometriosis stromal cells. Both of these may be important mechanisms in the pathogenesis of endometriosis, and it has been suggested that TNF-α is one of the essential factors for the pathogenesis and maintenance of endometriosis. Concentrations of TNF-α in peritoneal uid are higher in women with endometriosis than in patients with normal pelvic anatomy and peritoneal uid TNF-α concentrations correlate with the stage of endometriosis. Serum TNF-α levels also are significantly increased in patients with endometriosis, especially in early stages of the disease. Also, TNF stimulates the expression of prostaglandin synthase-2, which in turn increases the production of prostaglandins E2 and

Endometriotic implants contain both estrogen and progesterone receptors and respond to changes of hormonal levels with bleeding or production and release of inflammatory mediators, especially prostaglandins E2 and F. For a long time, it has been thought that prostaglandins are involved in endometriosis-related severe dysmenorrhea, and probably dyspareunia and nonmenstrual pelvic pain. Some of the data suggest that endometriotic lesions actually may produce greater amounts of prostaglandins than does eutopic endometrium. In fact, prostaglandins in endometriosis were produced mainly by Cox-2 (38- 40). Matsuzaki et al. found higher levels of Cox-2 in the epithelium and the stroma of endometriosis than in normal endometrium from controls without endometriosis. They also found higher levels of Cox-2 in the stroma of eutopic endometrium of women with endometriosis than in the stroma of women without endometriosis (41). Ota et al. have published similar results, showing higher levels of Cox-2 in endometriosis than in endometrium from controls. These data support the conclusion that Cox-2 is induced by

F2a, an indirect mechanism by which TNF may cause inflammatory pain (33-37).

endometriosis and leads to higher levels of prostaglandins (42).

**5.9 Clinical association between endometriosis and autoimmune diseases** 

Clinical conditions associated with endometriosis by patients, providers, and researchers alike have included headaches, arthralgias and myalgias, allergies, eczema, hypothyroidism,

in endometriosis (31).

**5.8 Immunologic factors** 

proliferation, inflammation and angiogenesis (32).

#### **5.4 Induction theory**

The theory of endometrial stem cells or transient amplifying progenitor cells claims that circulating stem cells originating from bone marrow or from basal layer of endometrium could differentiate into endometriotic tissue at different anatomical sites (24). In vitro studies have demonstrated the potential for ovarian surface epithelium, in response to estrogens, to undergo transformation to form endometriotic lesions. Although many putative factors have been identified, their propensity to cause endometriosis in some women but not in others demonstrates the still unidentified etiology of this disease (25).
