**6.1 Genetic factors**

Endometriosis regarded as a genetic disease due, apparently, to its reported familial aggregation. Yet even the reported familial aggregation, when examined closely, may be debatable and there has been little progress regarding the identification of genetic variants that predispose women to endometriosis. First degree relatives of patients with endometriosis have a 6.9% incidence of endometriosis in comparison with a 1% risk in controls (47).

There is a prevailing view that endometriosis is a polygenic disease and, as such, genetic polymorphisms that predispose women to endometriosis can be identified through linkage or association studies. In the last decade, numerous large-scale gene expression profiling studies have demonstrated, unequivocally, that many genes such as oncogenic K-ras are deregulated in endometriosis. Yet despite many publications, seemingly little headway has been made in elucidating the specific genetic factors that have a major impact on the risk of developing endometriosis. Few, if any, positive findings from genetic association studies have been replicated, and those who tried to replicate previously reported positive findings often end up with negative results. Not surprisingly, three meta-analyses on association of endometriosis and some genetic polymorphisms coding for dioxin detoxification enzymes, sex steroid biosynthesis and their receptors found no evidence of association even though meta-analyses known to have upward biases in risk estimates, especially the 'winner's curse' of first reports (48-49).

### **6.2 Environmental factors and dioxin**

Environmental factors, such as dioxin, might interact with multiple genetic susceptibility loci to produce the phenotype of endometriosis. Most of these environmental contaminants exhibiting estrogenic effects will lead to endocrine disruption through various environmental media such as food and water. Dietary intake of dioxin-like compounds with biological activity will increase the body burden (the total amount of these chemicals that are present in the human body at a given point in time), which might contribute to the pathogenesis of endometriosis. In addition, these chemicals can pass through the placenta to affect fetal environment. In a prospective cohort study, the rate of laparoscopically confirmed endometriosis was 80% greater among women exposed in utero to diethylstilbestrol (a synthetic estrogen originally prescribed in pregnancy to prevent miscarriage) after 10 years of follow-up. However, the relationship between endocrine

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

Endometriosis regarded as a genetic disease due, apparently, to its reported familial aggregation. Yet even the reported familial aggregation, when examined closely, may be debatable and there has been little progress regarding the identification of genetic variants that predispose women to endometriosis. First degree relatives of patients with endometriosis have a 6.9% incidence of endometriosis in comparison with a 1% risk in

There is a prevailing view that endometriosis is a polygenic disease and, as such, genetic polymorphisms that predispose women to endometriosis can be identified through linkage or association studies. In the last decade, numerous large-scale gene expression profiling studies have demonstrated, unequivocally, that many genes such as oncogenic K-ras are deregulated in endometriosis. Yet despite many publications, seemingly little headway has been made in elucidating the specific genetic factors that have a major impact on the risk of developing endometriosis. Few, if any, positive findings from genetic association studies have been replicated, and those who tried to replicate previously reported positive findings often end up with negative results. Not surprisingly, three meta-analyses on association of endometriosis and some genetic polymorphisms coding for dioxin detoxification enzymes, sex steroid biosynthesis and their receptors found no evidence of association even though meta-analyses known to have upward biases in risk estimates, especially the 'winner's

Environmental factors, such as dioxin, might interact with multiple genetic susceptibility loci to produce the phenotype of endometriosis. Most of these environmental contaminants exhibiting estrogenic effects will lead to endocrine disruption through various environmental media such as food and water. Dietary intake of dioxin-like compounds with biological activity will increase the body burden (the total amount of these chemicals that are present in the human body at a given point in time), which might contribute to the pathogenesis of endometriosis. In addition, these chemicals can pass through the placenta to affect fetal environment. In a prospective cohort study, the rate of laparoscopically confirmed endometriosis was 80% greater among women exposed in utero to diethylstilbestrol (a synthetic estrogen originally prescribed in pregnancy to prevent miscarriage) after 10 years of follow-up. However, the relationship between endocrine

reported interesting serologic parallels (43-46).

**6. Risk factors 6.1 Genetic factors** 

controls (47).

curse' of first reports (48-49).

**6.2 Environmental factors and dioxin** 

disrupting chemicals and endometriosis remains controversial because of lack of studies with sufficient statistical power (50-54).

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

#### **6.3 Anatomic defects**

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 endometriosis (58, 59).

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 an environment for induction of progressive endometriosis (63).

#### **7. Patient symptoms**

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

Endometriosis 13

(IBS) is worthy of particular attention (70). Crohn's disease should also be considered in the differential diagnosis of endometriosis, since this condition shows several similarities regarding both the locations and the anatomo-pathologic pattern (71). Although rare, familial Mediterranean fever (FMF) should be considered in the differential diagnosis of endometriosis (72). Rarely the presence of parasitic infestations has been reported in women

To exclude other causes of pelvic pain, laboratory investigations are often undertaken. Initially, a complete blood count (CBC), urinalysis and urine cultures, vaginal cultures, and cervical swabs may be obtained to exclude infections or sexually transmitted infections that

Although concentrations of the cancer antigen CA125 are slightly raised in some women with endometriosis, the test neither excludes nor diagnoses endometriosis and is not considered useful in establishing the diagnosis. The threshold for surgery is unlikely to be influenced by the CA125 concentration and the guidelines from the Royal College of Obstetricians and Gynecologists described CA125 as having only limited value as either a

Endometriomas are uncommon in the adolescent population, and information regarding the adnexa can be obtained noninvasively with a pelvic ultrasound. Ultrasound as the primary imaging investigation can aid in its diagnosis. Transvaginal ultrasound (TVUS) with color flow Doppler can detect endometriomas with a high degree of accuracy. Ultrasound is

MRI is an excellent imaging modality for the evaluation of patients with deep pelvic endometriosis, showing high accuracy in the diagnosis and prediction of disease extent. The MRI diagnosis of deep pelvic endometriosis is based on the conjoint presence of signal intensity and morphologic abnormalities in the anterior and posterior compartments of the pelvis and the presence of surrounding fibrosis. The use of endovaginal and rectal contrast is useful to better delineate the anatomy and map out the extent of disease. Atypical locations of deep pelvic and extrapelvic endometriosis have been presented and grouped under the term anterior endometriosis. An accurate diagnosis therefore resides in clinical awareness and systematic review via MRI. A key finding of malignant transformation is the presence of enhancing nodules in the endometrial cyst on T1-weighted images (74, 75).

Laparoscopy is the gold standard for the diagnosis and staging of endometriosis and allows for curative surgical resection at the same time. Patients found to have endometriosis at the time of laparoscopy should either be treated through surgical ablation, resection, or laser treatment. In addition, biopsy is recommended, as lesions of endometriosis in adolescents often take on a different appearance as compared with the typical powder-burn lesions seen in adults. Interestingly, clear or red endometriotic lesions are much more commonly seen in

limited in its ability to detect small peritoneal implants and adhesions (74).

with symptoms suggestive of endometriosis (73).

may cause pelvic inflammatory disease (63).

screening or a diagnostic test (15).

**12. Laparoscopic findings** 

the adolescent population (76).

**11. Imaging and endometriosis** 

**10. Laboratory testing** 

classification of endometriosis, which describes the extent of disease bulk, poorly predicts symptoms. Thus clinically, women with extensive disease (stage IV) may note few complaints, whereas those with minimal disease (stage I) may have significant pain or subfertility or both (68, 69).

The following symptoms can be caused by endometriosis based on clinical and patient experience:


However, the predictive value of any one symptom or set of symptoms remains uncertain as each of these symptoms can have other causes. A large group of women with endometriosis is completely asymptomatic. In these women endometriosis remains undiagnosed or is diagnosed atlaparoscopy for another indication. A subset of women with more advanced disease, ovarian or deep invasive rectovaginal endometriosis, is asymptomatic as well. This makes the development of guidelines for the diagnosis and the therapy rather cumbersome. Endometriosis should be suspected in women with dysmenorrhoea, deep dyspareunia, acyclic chronic pelvic pain and/or subfertility.
