striata Zucc ssp striata (“Tha’mni”, “Junquillo”)

Endometriosis is a benign, chronic disorder defined by abnormal growth of endometrium outside of the uterine cavity.45

The disease was first defined by the general surgeon Thomas Cullen.46 _{He recognized the two key features: i) the} presence of endometrial glands and stroma outside of the uterine cavity and ii) ectopic endometrial glands and stroma were benign and non-neoplastic in nature.

1.2.1: Epidemiology

Endometriosis is a significant cause of female infertility and morbidity. A surgical examination is required for diagnosis, and for that reason the true prevalence remains controversial. In asymptomatic women undergoing tubal ligation, the prevalence is

thought to be about 4%, (range 1-7%).47 The disease should be suspected in women suffering from pelvic pain and primary infertility, present in 50%-60% and 17% respectively.48,49 On average it is estimated 10% of reproductive women suffer from endometriosis, whether the disease is symptomatic or not.50

1.2.2: Clinical features

Endometriosis paints a variable clinical picture and clinical features rely largely on position of ectopic lesions. Typically, the presenting complaint is pain. This is usually chronic, presenting itself in the form of dysmenorrhoea or dyspareunia. Pain can be cyclical or continuous, and dull or throbbing. Patients commonly report a burning or hypersensitivity, suggesting a neuropathic component.51 Pain is often accompanied by bowel symptoms such as dyschezia. However, patients can be asymptomatic and the presenting complaint may be a difficulty to conceive. A bimanual examination usually reveals focal pain/tenderness and/or a fixed retro-

verted uterus. Due to the variation of presentation, there is considerable overlap with other gynaecological and non-gynaecological diseases such as inflammatory bowel disease and depression, making diagnosis challenging. On average it is estimated the time from initial symptoms to diagnosis is over ten years.52

1.2.3: Investigations

Non-invasive investigations such as magnetic resonance imaging (MRI) and trans- vaginal ultrasound (TVS) have a 80-90% sensitivity and 60-98% specificity at detecting ovarian endometriomas but results are less impressive when detecting lesions at other locations.53 Ca-125 can be elevated but again this has poor sensitivity and specificity.54 Surgical visualisation followed by histological confirmation remains the gold standard.55

1.2.4: Pathology and staging

Endometriosis is an oestrogen dependant disease; lesions consequently wane throughout pregnancy, menopause and menstruation. Conversely, there are reports of endometriosis being present in males, and women suffering from Turner’s syndrome.56,57 However, in both these cases patients were taking exogenous hormones, and thus enabled ectopic growth. Ectopic lesions are commonly found on the ovaries, fallopian tubes, pelvic peritoneum and bladder. Lesions can be observed in distant organs such as the lung, although admittedly these cases are rare.58 Within endometriosis, three ‘sub-diseases’ are thought to exist: peritoneal, ovarian and rectovaginal.59 Red lesions, ‘powder-burn’, white lesions, ‘chocolate cysts’ and microscopic lesions, are all descriptors of this disease’s variable form. Lesions comprise endometrial glands and stroma, although appearance is somewhat

dissimilar to eutopic tissue (Figure 1.5). Ectopic glands are usually less organised and less differentiated. Morphology and histochemical data suggest ‘red’ lesions best resemble proliferative eutopic endometrium, proposing these represent early implantation and disease.59 Irritation of ‘menstruating’ red lesions leads to an inflammatory response within the pelvic cavity, producing fibrosis, which ultimately leads to adhesions and distortion of pelvic anatomical structures. Ovarian endometriosis typically produces cysts in the form of endometriomas, and recto- vaginal lesions are rich in smooth muscle with sparse stroma.

Histological analysis suggests that increased angiogenesis and neural infiltration are also significant features of endometriosis. An Australian group discovered neurons are increased in eutopic tissue from women with endometriosis, compared to those without.60 This could be the reason why pain is the dominant symptom, and is consistent with other work.61-63 The reasons and mechanisms behind increased angio- and neurogenesis remain unclear. There are reports of increased angiogenic and

50µ m

Figure 1.6: Ectopic endometriotic gland and stroma. Haemotoxylin and Eosin staining of a well differentiated ectopic gland, consisting of endometrial epithelia and stroma.

neural growth factors in the pelvic fluid of women with endometriosis compared to those without. This has resulted in a shift in thinking; endometriosis may not be just a gynaecological disorder, but indicative of a systemic problem.64,65

The cause of infertility is two-fold. Adhesion formation can result in distortion and loss of patency of the fallopian tubes. However, in women without adhesions fertility is still reduced; differences on a cellular level in eutopic endometrium are thought to be responsible. The American Society for Reproductive Medicine (ASRM) have developed a staging system to describe the extent of endometriosis and this correlates well with infertility (Table 1.1).

1.2.5: Endometriosis and Malignancy

Although endometriosis is a benign condition, it shares common characteristics with malignant cells.66 Like cancer, endometriosis involves ‘metastatic spread’ attaching and damaging local and distant tissues.67 A recent study, investigated differences in metastatic inducing proteins (MIPs) between eutopic endometrium from patients with endometriosis and those without. Immuno-histochemical and polymerase chain

Stage 1 (Minimal) Findings restricted to only superficial lesions and possibly a few filmy adhesions

Stage II (Mild) As above, some deep lesions are present in the cul-de-sac

Stage III (Moderate)

As above, plus presence of endometriomas on the ovary and more adhesions