**5.6 Hormonal effect**

Endometriosis is an estrogen-dependent disorder. Aberrant production of estrogen by endometriotic stromal cells is indispensable for the development and maintenance of endometriosis especially during the period of menstruation when no ovarian estrogen is available. This notion was supported by identification in endometriotic stromal cells of the presence of all proteins/enzymes required for denovo synthesis of estrogen:steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage enzyme (P450scc), 3b-hydroxy steroid dehydrogenase (3b-HSD), 17 a-hydroxylase 17,20 lyase, P450 aromatase and 17b-HSD type1. Among these enzymes, StAR and aromatase control the first and last committed steps in the biosynthesis of estrogen. StAR transports cholesterol across the mitochondrial membrane to the inner mitochondrial leaflet, where the first enzymatic reaction occurs. Aromatase catalyses the conversion of androstenedione to estrone. Estrone is further converted to 17b-estradiol (normally referred to a sestrogen) by 17b-HSD type1, whereas 17b-HSD type2 reverses this process. In disease-free uterine endometrium, no StAR or aromatase are detected but there are increased StAR and aromatase levels in extra-ovarian endometriotic implants and endometriomas. In addition, the absence of 17b-HSD type2 in pelvic endometriotic implants further favors an increase in the local concentration of estrogen (28-30).

#### **5.7 Steroid receptor genetics**

Endometriosis is an estrogen-dependent disease. The action of steroids such as estrogen, progesterone and androgen are mediated through their respective receptors (SRs). SRs are ligand (hormone)-dependent transcription factors. Upon activation with the specific hormone they can interact with hormone response elements in the promoter of target genes. Since the action of steroids such as estrogen, progesterone and androgen are mediated through their respective receptors - Estrogen Receptors (ER), Progesterone Receptors (PR)

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).

Evidence also supports the concept of endometriosis originating from aberrant lymphatic or vascular spread of endometrial tissue. Findings of endometriosis in unusual locations, such as the perineum or groin, bolster this theory. The lymphatic and hematogenous spread of endometrial cells can explain the presence of endometriosis in the pelvis or elsewhere. However, in the last few years, strong evidence indicates the possible role of immunologic factors and the lack of adequate immune surveillance in the pathogenesis of endometriosis

Endometriosis is an estrogen-dependent disorder. Aberrant production of estrogen by endometriotic stromal cells is indispensable for the development and maintenance of endometriosis especially during the period of menstruation when no ovarian estrogen is available. This notion was supported by identification in endometriotic stromal cells of the presence of all proteins/enzymes required for denovo synthesis of estrogen:steroidogenic acute regulatory protein (StAR), P450 side-chain cleavage enzyme (P450scc), 3b-hydroxy steroid dehydrogenase (3b-HSD), 17 a-hydroxylase 17,20 lyase, P450 aromatase and 17b-HSD type1. Among these enzymes, StAR and aromatase control the first and last committed steps in the biosynthesis of estrogen. StAR transports cholesterol across the mitochondrial membrane to the inner mitochondrial leaflet, where the first enzymatic reaction occurs. Aromatase catalyses the conversion of androstenedione to estrone. Estrone is further converted to 17b-estradiol (normally referred to a sestrogen) by 17b-HSD type1, whereas 17b-HSD type2 reverses this process. In disease-free uterine endometrium, no StAR or aromatase are detected but there are increased StAR and aromatase levels in extra-ovarian endometriotic implants and endometriomas. In addition, the absence of 17b-HSD type2 in pelvic endometriotic implants further favors an increase in the local concentration of

Endometriosis is an estrogen-dependent disease. The action of steroids such as estrogen, progesterone and androgen are mediated through their respective receptors (SRs). SRs are ligand (hormone)-dependent transcription factors. Upon activation with the specific hormone they can interact with hormone response elements in the promoter of target genes. Since the action of steroids such as estrogen, progesterone and androgen are mediated through their respective receptors - Estrogen Receptors (ER), Progesterone Receptors (PR)

**5.4 Induction theory** 

(26, 27).

**5.6 Hormonal effect** 

estrogen (28-30).

**5.7 Steroid receptor genetics** 

**5.5 Lymphatic or vascular spread** 

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 in endometriosis (31).

#### **5.8 Immunologic factors**

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 proliferation, inflammation and angiogenesis (32).

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

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 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,

Endometriosis 11

disrupting chemicals and endometriosis remains controversial because of lack of studies

Several excellent reviews have been published characterizing dioxins. Chemically, dioxin, an abbreviation of 2, 3, 7, 8-tetrachloro-dibenzo-p-dioxin, or TCDD, is a polycyclicaromatic agent with chloral substituent. Dioxin is a lipophilic material that could accumulate in tissues with a high fat content. There is insufficient evidence at this moment in support of the hypothesis that dioxin exposure may lead to increased risk of developing endometriosis in women. Dioxins may act similarly to estrogen in estrogen-target tissues such as endometrium (eutopic or ectopic), promoting proliferation. However, it should be noted that in the presence of Aryl hydrocarbon Receptor (AhR) agonists, the function of liganded ER is attenuated. Since the local estrogen production is increased in endometriosis due to aberrant regulation of aromatase and of type 2 17 b-hydroxy steroid dehydrogenase, it is unclear what the net effect

Reproductive outflow tract obstruction can predispose to development of endometriosis, likely through exacerbation of retrograde menstruation. Accordingly, endometriosis has been identified in women with noncommunicating uterine horn, imperforate hymen, and transverse vaginal septum. Because of this association, diagnostic laparoscopy to identify and treat endometriosis is suggested at the time of corrective surgery for many of these anomalies. Repair of such anatomic defects is thought to decrease the risk of developing

A number of Mullerian anomalies, most importantly those associated without flow tract obstruction, are associated with endometriosis. In a series by Schifrin et al. 15 patients (40%) younger than 20 years of age with endometriosis had a genital tract anomaly (60). This is opposed to findings by Goldstein et al who noted congenital anomalies in only 11% of 74 teenagers with endometriosis (61). The clinical course of endometriosis associated with reproductive tract anomalies is quite different from that in the adult. Sanfilippo et al described a series of patients with extensive endometriosis in association with outflow tract obstruction (62). Once correction of the outflow tract occurred, there was virtually 100% reversal of intra-abdominal endometriosis on follow-up laparoscopy. It is thought that the pathophysiology of the disease process is different in the adult as compared with adolescents with an outflow tract obstruction. Interestingly, the fact that many adolescents without flow tract obstruction show significant endometriosis at the time of laparoscopy does support the theory of retrograde menstruation as an etiology for development of endometriosis. However, given that endometriosis resolves without further treatment after correction of the outflow tract abnormality suggests that retrograde menstruation, in and of itself, is not sufficient to induce a state of progressive endometriosis. Other factors besides retrograde menstruation, such as immune system defects, may be fundamental to creating

Although women with endometriosis may be asymptomatic, symptoms are common and typically include chronic pelvic pain and infertility. As previously stated, the current ASRM

of AhR agonists such as dioxins is on ectopic endometrium (55-57).

an environment for induction of progressive endometriosis (63).

with sufficient statistical power (50-54).

**6.3 Anatomic defects** 

endometriosis (58, 59).

**7. Patient symptoms** 

fibromyalgia, chronic fatigue syndrome, and susceptibility to vaginal candidiasis. These often ill-defined entities carry an allure of mystery, paralleling many nonspecific symptoms encountered by patients with known autoimmune disease. Because of this parallelism, and with no alternative explanation for a patient's extraperitoneal symptoms, patients and health care providers may suspect an immunopathologic mechanism. The potential link between autoimmune disease and endometriosis has been studied from a number of perspectives. Some investigators have reported common clinical elements among patients with endometriosis and patients with various autoimmune processes, whereas others have reported interesting serologic parallels (43-46).
