Endometriosis is a chronic oestrogen-dependent condition that affects 10% of women from puberty to menopause. It is characterised by the presence and proliferation of endometrial-like cells outside the uterine cavity, generally within the pelvis. Endometriosis can present as superficial or deep peritoneal lesions, ovarian endometrioma or deep rectovaginal disease. The two hallmark symptoms of endometriosis are pelvic pain and infertility resulting in poor quality of life. There is no correlation between the extent of the disease and severity of symptoms. The true prevalence of the condition is not known, as it requires a laparoscopy to confirm the diagnosis. It is found in up to 30% of women with infertility and in 45% of those with pelvic pain. While there are several theories of pathogenesis, an interplay of genetic, hormonal, environmental and immunological factors is implicated in the development of endometriosis in susceptible women. Symptoms are managed with a combination of hormonal treatment and laparoscopic ablation or excision of lesions for pain and usually assisted reproduction for infertility. Endometriosis is prone to recurrence after treatment, requiring multiple contacts with healthcare and repeat surgery. Management of endometriosis requires an individualised approach based on the woman’s age, predominant symptoms and priorities, which are subject to change over time.
Endometriosis is a chronic gynaecological condition classically associated with dysmenorrhoea, pelvic pain and infertility, though some women can be asymptomatic. It is characterised by the presence and proliferation of endometrium-like tissue (glands and stroma) in ectopic sites outside the physiologically normal location of the uterine cavity . The diagnosis is established by direct visualisation of lesions at laparoscopy.
Lack of pathognomonic signs and symptoms of endometriosis combined with the need for laparoscopy to confirm the diagnosis make it challenging to estimate the disease burden. The true prevalence of endometriosis in the general population hence remains unknown, although estimates range between 2% and 10% in women of reproductive age group . The prevalence of endometriosis is significantly higher in women with pelvic pain or infertility, with reported rates varying between 20% and 50%. In a study of women undergoing laparoscopic sterilisation, the authors reported a 7% prevalence rate of endometriotic lesions in multiparous women. A multicentre Italian study  surveyed the prevalence of endometriosis in 3,684 women with selected gynaecological conditions requiring surgery. They reported that co-existing endometriosis was identified in 30% of women with infertility, 45% of women with pelvic pain, 35% of women with ovarian cysts and 12% of women with fibroids.
Several plausible theories regarding pathogenesis of endometriosis exist: some propose the origin of endometriosis from the uterine endometrium while others suggest an extrauterine origin for endometriotic implants. An increasing number of studies suggest an interplay of genetic, hormonal, environmental, immunological and oxidative factors in the development of endometriosis in susceptible women.
The classical theories of pathogenesis are:
1. Retrograde Menstruation (Sampson’s Theory) This is one of the most widely recognised theories for the genesis of endometriosis. In 1927, Sampson proposed the novel idea that ectopic endometrial tissue in the pelvis arises as a result of retrograde menstrual flow from the fallopian tubes into the abdominopelvic cavity. Presence of blood in the pelvis has been observed at surgical procedures in women during their menses. Animal models have confirmed that shed endometrial tissue has the ability to establish and grow outside the uterine cavity. The incidence of endometriosis is also higher in women with congenital anomalies associated with outflow tract obstruction that increase retrograde menstruation, such as an imperforate hymen or cervical stenosis.
2. Metaplastic Transformation (Meyer’s Theory) Meyer proposed that endometriotic cells in the peritoneum originate from metaplasia of coelomic epithelium as a result of unknown stimuli. This is plausible, as both the peritoneum and endometrium share a common embryonic precursor, the coelomic cell. This theory may explain the occurrence of endometriosis in women who have had a hysterectomy and even in men undergoing oestrogen therapy.
The ‘induction theory’ is an extension of the coelomic metaplasia theory and proposes that one or several endogenous, biochemical, or immunological factors may induce endometrial differentiation of undifferentiated cells.
3. Lymphatic or Haematogenous Spread (Halban’s Theory) Halban proposed that endometriotic tissue can disseminate from the uterus to distant and extrapelvic sites through the lymphatic or vascular systems. This theory provides an explanation for cases in which endometriosis is found in remote sites such as the brain or pleura, but does not explain the mechanisms that allow cells to establish and proliferate in these extrapelvic sites.
4. Direct Transplantation Theory According to this theory, endometrial cells may become incorporated at surgical sites (e.g. at the site of an episiotomy or a caesarean section) during tissue trauma or surgical procedures. The initiation of a localised oncogenic-like cascade and lack of immunological response may result in implant survival.
5. Theory of Mullerianosis : This theory purports that the embryonic mullerian rests retain the capacity to develop into endometriotic lesions under hormonal (oestrogen) and environmental influences.
More recently, differentiation of bone marrow stem cell lineages, such as mesenchymal or endothelial stem cells, into endometriosis has been proposed.
It is likely that various innate and acquired factors, such as genetics or environmental or immunological factors, acting in conjunction lead to the development of endometriosis in susceptible women. The different theories and mechanisms for the pathogenesis of endometriosis are depicted in Figure 3.1.
Figure 3.1 Theories of endometriosis pathogenesis.Reproduced with permission from .
Endometriosis is inherited in a polygenic manner. Several candidate genes have been implicated. Some of these genes encode detoxification enzymes and thus may increase susceptibility to environmental stimuli. Other explanations include an abnormal epigenetic signature in the eutopic endometrium of women with endometriosis, which creates an altered hormonal milieu and an increase in the local concentration of oestrogen, thereby promoting development of ectopic implants.
The peritoneal environment in most women is capable of resorbing menstrual debris at the end of menstruation. In women with endometriosis, constitutional or acquired anomalies in endometrial cells evade immune clearance, conferring a survival advantage. Dysregulation of cell mediated immunity, increased endometrial autoantibodies, higher levels of cytokines and activation of lymphocytes and macrophages have been observed in the peritoneal fluid of women with endometriosis. Decreased cytotoxicity allows the shed endometrial tissue to establish itself, while activated macrophages produce a higher amount of cytokines and growth factors, promoting disease progression through neuroangiogenesis and vasculogenesis. Endometriosis is frequently associated with extensive peritoneal adhesions. There is evidence to suggest that this may be a result of an impaired fibrinolytic system.
Endometriotic lesions can be divided into three main types: peritoneal endometriosis, ovarian endometrioma and deep infiltrating endometriosis.
Peritoneal Endometriosis Peritoneal lesions are the most diverse in their morphological appearance and are classified as red (red, red-pink and clear), black (black and blue) and white (white, yellow-brown and peritoneal defects) lesions . Atypical and subtle lesions are also common, presenting as serous or clear vesicular implants. Clinical evidence suggests that these appearances represent different stages of peritoneal lesions, with temporal progression of lesions from red vesicular to blue-black powder burn to fibrotic with adhesional changes. Defects in the pelvic peritoneum, or lacunae, referred to as Allen–Masters windows, may arise secondary to adhesion formation from the cyclical inflammatory changes associated with the endometriotic lesions.
Endometrioma Ovarian involvement typically presents as cysts progressively increasing in size and filled with chocolate coloured fluid – often referred to as ‘chocolate cysts’ or ovarian endometrioma classically adherent to pelvic side wall and the posterior aspect of uterus.
Deep Endometriosis Deep endometriosis is characterised by nodules extending more than 5 mm beneath the peritoneum and may involve the uterosacral ligaments, vagina, bowel, bladder or ureters. The depth of infiltration often correlates better with the type and severity of symptoms such as dyspareunia and dyschezia.
Figure 3.2 Phenotypic subtypes of peritoneal endometriosis.Reproduced with permission from .
Endometriotic lesions are predominantly confined to the abdominopelvic cavity in the pelvic peritoneum, ovaries, uterosacral ligaments or rectovaginal septum. Extrapelvic locations include surgical scars and the diaphragm or lungs, although other rare locations are possible. The anatomical distribution of endometriotic lesions is not even, with evidence of abdominopelvic, anterior–posterior and left–right asymmetry . They are more common in the pelvis than in the abdomen and have a predilection towards the pelvic cul-de-sac (the lowest part of the pelvis). This preferential location appears to be the result of the influence of gravity. Endometriosis is more common in the posterior compartment of the pelvis than the anterior compartment and in the left hemipelvis compared to the right. This distribution can be explained by the trajectory and direction of peritoneal flow and areas of stagnation of peritoneal fluid.
Endometriosis Classification The extent of the disease varies, from a few, small peritoneal lesions on otherwise normal pelvic organs, to large, ovarian endometrioma, adhesions or deep disease involving the uterosacral ligaments, large bowel and ureters, causing marked distortion of the pelvic anatomy. The best-known classification system for endometriosis is the revised American Society for Reproductive Medicine (r-ASRM) classification (1997). Depending on the extent and location of the disease, r-ASRM have classified endometriosis into four stages: minimal, mild, moderate, and severe, or stage I to IV. Other emerging systems include the Enzian classification for deep endometriosis and the endometriosis fertility index (EFI). All these classification systems have attracted criticism because of the poor correlation with disease symptoms as well as a lack of predictive prognosis for pain or infertility or response to treatment. The r-ASRM has been the oldest and most used system, though EFI has a better prognostic value for pregnancy rates because the latter includes clinical variables in addition to the surgical findings in the clinical scoring.
The majority of the risk factors for endometriosis relate to the concept that endometriosis is an oestrogen-dependent condition, associated with reflux of menstrual effluent into the peritoneal cavity .
Age Endometriosis is typically found in women of reproductive age with the peak age for diagnosis being 25–29 years. The age of onset is likely to be earlier as there is usually a significant delay between a woman’s first presentation to primary care and a confirmed diagnosis of endometriosis. This interval has been reported to be around 8 years in the United Kingdom.
Menstrual and Reproductive Factors Early menarche (age <12 years), a short interval between cycles and heavy menstrual flow have been consistently shown to be associated with an increased risk of endometriosis. This is related to increased exposure to menstrual efflux, strongly supporting Sampson’s theory.
Dysmenorrhoea has a very strong link with endometriosis. Up to 50% of adolescent girls with severe dysmenorrhoea are diagnosed with endometriosis. Dysmenorrhoea may well be considered a symptom of the disease. An alternative explanation, that dysmenorrhoea is likely to be associated with some degree of outflow obstruction and a higher propensity to retrograde menstruation, potentially allows dysmenorrhoea to be classed as an independent risk factor for the development of endometriosis.
Association with parity is more complex, as infertility may be either a consequence or cause of the disease. An inverse association of endometriosis with parity is well established. Pregnancy and lactation are associated with a period of amenorrhoea, reducing exposure to menstrual endometrium. High progesterone levels present in pregnancy inhibit the establishment and growth of endometriotic deposits.
Race, Ethnicity and Social Class There is a non-validated clinical impression that endometriosis may vary with race, with black women having a lower rate of endometriosis and South-East Asian women having a higher rate than Caucasian women. A higher frequency of endometriosis is reported among women of higher social class. This may be influenced by diagnostic bias resulting from increased health awareness and better access to health care.
Smoking, Diet and Lifestyle Factors There is some evidence that smoking has a protective effect on endometriosis due to its anti-oestrogenic effect. Smoke compounds impair oestradiol and progesterone synthesis. Smoking, on the other hand, is proinflammatory and can trigger inflammation associated with endometriosis. A meta-analysis of 38 studies did not support any link between smoking and the risk of endometriosis . Moderate alcohol consumption has been found to increase the risk of endometriosis. This effect is mediated through an increase in oestrogen levels secondary to increased aromatase activity or the impact of alcohol on release of luteinising hormone (LH) from the pituitary. A recent meta-analysis demonstrated a 1.2 times higher risk of endometriosis in women with regular alcohol intake compared to those who did not consume alcohol, with evidence supporting an argument for a dose-dependent relationship . Data on the link between caffeine and endometriosis are insufficient. Caffeine inhibits aromatase, thereby reducing conversion of androgens to oestrogen. A protective effect of caffeine on endometriosis risk has not yet been confirmed.
Regular exercise or physical activity confers a protective effect on endometriosis by decreasing oestrogen production, reducing the levels of bioavailable oestrogen by an increase in levels of serum hormone binding globulin (SHBG) and increasing systemic levels of anti-inflammatory cytokines. The positive effect of exercise on the reduced risk of endometriosis has been noted in a number of studies, although bias introduced through study design and selection of controls limits definitive interpretation.
Constitutional and Genetic Factors A literature review identified a modest, inverse relationship between adult BMI and risk of endometriosis. Likewise, taller women have higher follicular phase oestradiol and thereby a higher incidence of endometriosis.
Familial aggregation of endometriosis has been noted in population-based samples and twin studies. An up to six-fold increase in the risk of endometriosis is noted in the first-degree relatives of affected women with a polygenic pattern of inheritance. A strong familial tendency in non-human primates lends further support for a genetic predisposition.