Transformation of coelomic epithelium

This theory, first described by Meyer (1919), postulated the possibility of differentiation by metaplasia towards an endometrial-like tissue of the original coelomic membrane following prolonged irritation and oestrogen stimulation. It is proposed that these adult cells undergo dedifferentiation back to their primitive origin and then transform to endometrial cells. If this theory is correct, metaplasia should occur wherever coelomic membranes are present. This theory has many attractions which could explain the occurrence of endometriosis in nearly all the ectopic sites in the presence of aberrant Müllerian cells. What induces this transformation — whether it is hormonal stimuli, inflammatory irritation or other processes — is uncertain. If coelomic metaplasia is similar to metaplasia elsewhere, the frequency of the disorder should increase with advancing age. The clinical pattern of endometriosis is distinctly different from this, with an abrupt halt in the disease with the cessation of menses at the menopause and reduced oestrogen production, thus raising some questions over this theory.

Menstrual regurgitation and implantation (metastatic theory)

As early as 1927, Sampson proposed the metastatic theory, postulating that retrograde menstrual flow transported desquamated endometrial fragments through the fallopian tubes into the peritoneal cavity (Sampson 1927). Once there, the still viable cells subsequently implanted and began growth and invasion. In support of this theory, experimental endometriosis has been induced in animals with replacement of menstrual fluid or endometrial tissue in the peritoneal cavity. Supporting this theory in humans is the finding that endometriosis is commonly found in young girls with associated abnormalities in the genital tract causing obstruction to the outflow of menstrual fluid (Schifrin et al 1973). Halme et al (1984) observed bloody fluid at the time of menstruation in the pelvis during laparoscopic assessment, but as this finding occurs in up to 90% of all women, it is regarded as a physiological phenomenon. The high incidence of retrograde menstruation suggests that this phenomenon alone does not give rise to endometriosis, but that some other factor(s) must be involved in development of the disease. These factors could include some alteration in the (uterine) endometrium, altered immune response to retrograde menstruation (hence failure to clear the peritoneal cavity of debris efficiently), or a more favourable peritoneal environment which may stimulate the growth and implantation of ectopic endometrium within the peritoneal cavity itself.

Genetic and immunological factors

Many studies have indicated that there may be a genetic factor related to endometriosis since the disease is more prevalent in certain families. It has been shown that women with an affected first-degree relative have a seven times higher risk of developing endometriosis, which may be severe (Simpson et al 1980, Halme et al 1986). Endometriosis is also more common in monozygotic twin sisters than dizygotic twins, but no association was found with specifically identified tissue types (Simpson et al 1984). Whilst Dmowski et al (1981) demonstrated a decreased cellular immunity to endometriotic tissue in women with endometriosis, no clinically significant immune system abnormality has been observed in women with the disease; hence, the precise genetic or immune components increasing an individual’s potential to develop this disorder are yet to be defined.

Vascular and lymphatic metastasis (Halban’s theory)

Halban’s theory suggests that distant endometriosis (outwith the abdominal cavity) occurs via vascular or lymphatic spread of viable endometrial cells or fragments. The theory would explain the rare occurrence of endometriosis in lung, limbs and brain, but not in more common sites within the peritoneal cavity and pelvis.

Endometrial disease theory

Many view the superficial implants as ‘physiological’ lesions which may regress spontaneously. Deep infiltrating lesions and ovarian endometriotic cysts are pathological and arise from cells that have undergone somatic mutations. Such mutations may have been produced by environmental factors (e.g. pollutants, dioxins). These abnormal cells then develop into a ‘benign tumour’ consisting of endometriotic glands and stroma. For a review on environmental factors in the aetiology of endometriosis, the reader is directed to Missmer and Mohllagee (2008).

Further support of the above theory stems from biochemical differences demonstrated in the endometrium in patients with and without endometriosis (Guidice and Kao 2004). These include differences in the expression of metalloproteinases, tumour susceptibility genes and angiogenic factors. Such changes may allow certain types of retrograde endometrial fragments to implant more readily than others, and this may be due to an underlying inherited genetic tendency.

Iatrogenic dissemination

Transplantation of endometrial cells can occur during gynaecological surgical procedures. This would explain the development of endometriotic nodules in abdominal wall scars following caesarean section, myomectomy and hysterectomy, and in laparoscopic port scars. In addition, implantation at perineal repair can cause endometriosis to develop in episiotomy scars.

Conclusion

The conclusion reached from the above theories is that pelvic endometriosis is probably a consequence of transplantation of viable endometrial cells regurgitated at the time of menstruation from the fallopian tubes into the peritoneal cavity. In addition, transport of endometrial cells may occur by other routes (some iatrogenic). It is unclear whether endometriotic implants are derived from in-situ pluripotential cells generated by metastatic seeding, but it is known that endocrine and immunological factors allow growth and spread within the pelvis and neighbouring organs. Delayed childbearing, either by choice or infertility, has been implicated as a risk factor for the development of endometriosis. The risk of developing endometriosis also corresponds with cumulative menstruation, menstrual frequency and volume. Women with shorter menstrual cycles of less than 27 days and longer flows (more than 7 days) are twice as likely to develop the disease compared with women with longer cycles and shorter flows. Thus, many components are necessary to allow endometriotic deposits to implant and subsequently grow (Figure 33.1).

Figure 33.1 Suggested aetiological factors in the pathogenesis of endometriotic implants.

The cell-mediated efferent arm of the immune system controls implantation or rejection of such fragments. In most women, these fragments are not in a favourable state or in a favourable environment for implantation, and are engulfed by macrophages and thus disposed. In women with deficient or altered cell-mediated immunity, implantation of the ectopic fragments allows implantation to occur with subsequent development of endometriotic implants. Such immune changes could be transmitted genetically and could be both qualitative and quantitative, resulting in variable ages of onset, extent and duration of expression. Autoantibody production would be a secondary phenomenon, developing as the number and extent of endometriotic deposits increase.

Peritoneal macrophages

Normal peritoneal fluid contains approximately 10⁶ cells per ml; 90% are macrophages, and the remainder are lymphocytes and desquamated mesothelial cells. The role of peritoneal macrophages in women with endometriosis has been the source of much interest, and women with endometriosis associated with infertility have been reported to have significantly higher concentrations of macrophages in peritoneal fluid than either fertile women or infertile women without endometriosis. Macrophages in patients with endometriosis appeared to be highly phagocytic against spermatozoa in vitro compared with those from fertile women or infertile women without endometriosis (Muscato et al 1982). In addition, they are also able to survive better in vitro than those from fertile controls (Halme et al 1986). Peritoneal fluid from patients with endometriosis has also been shown to have a cytotoxic effect on in-vivo cleavage of mouse embryos. These findings on the quantitative and qualitative properties of macrophages in peritoneal fluid may partially explain the mechanisms of infertility in patients with endometriosis.

Prostaglandins and prostanoids

The role of prostaglandins and their metabolites in peritoneal fluid in the pathogenesis and symptomatology of endometriosis is controversial. It has been reported that increased levels of prostaglandin F_2α (PGF_2α) are found in the peritoneal fluid of patients with the disease (Meldrum et al 1977). In addition, increased peritoneal fluid volume and increased concentrations of the prostaglandin metabolites thromboxane B₂ and 6-keto PGF_2α have been noted. Other investigators have found no increase in either the volume of peritoneal fluid or its concentrations of prostaglandins or metabolites (Rock et al 1982). These conflicting reports may reflect the timing of peritoneal fluid sampling and difficulties in assay measurement of the small quantities of substrates, all of which have very short half-lives.

In recent years, it has been appreciated that more subtle forms of endometriosis may be present with only minimal evidence of visual changes in the peritoneum. However, if there are changes in the prostaglandin content of the peritoneal fluid, the mechanisms by which these changes influence endometriosis or its association with infertility remain unclear.

Cytokines and growth factors

A large number of cells, including macrophages, lymphocytes, fibroblasts and epithelial cells, synthesize a wide range of polypeptides of high biological activity within the cytokine/growth factor group. They have multiple effects including the regulation of differentiation, growth and function of a wide variety of cell types. It was generally believed that cytokines were produced in increased amounts as part of the inflammatory process or as part of a response to infection or immune challenge. Cytokines are very potent and active at picogram to nanogram levels, and are difficult to detect and identify. Research activity has been concentrated on the measurement of various cytokines including various interleukins, colony stimulating factors, human necrosis factor and transforming growth factors. To date, no consistent changes between normal, infertile women with and without endometriosis and patients with endometriosis who are not infertile have been reported to satisfactorily explain the aetiology or pathogenesis of the disease.

Peritoneal environment: conclusions

Peritoneal macrophages play an important role in the peritoneal cavity where endometrial tissue fragments often arrive and are likely to adhere to the mesothelial lining. The adherence may be mediated by cell adhesion molecules and other factors produced by activated macrophages. Endometrial tissue will potentially adhere if the regurgitated amount of the tissue is too great, or if the capacity of the intra-abdominal cells to clear the cellular debris is in any way impaired. Once an endometrial fragment has gained adherence, further tissue growth may be promoted by steroids, cytokines, growth factors and angiogenic factors present in peritoneal fluid in a paracrine and autocrine fashion.

Dysmenorrhoea

Dysmenorrhoea is the most common presenting symptom, affecting 70–80% of women with proven endometriosis. Dysmenorrhoea often occurs with pelvic pain, but patients commonly describe a background of constant dragging, aching pain which may be exacerbated by the menses but is often a different type of pain from the typical cramping nature of spasmodic dysmenorrhoea and often in a different site. Typically, pain starts some days before menstruation as an ache or discomfort, similar to congestive pelvic pain. It worsens and becomes spasmodic with the start of the menses and continues throughout days of bleeding, lessening as menstrual flow ebbs. Unlike ‘primary dysmenorrhoea’ which starts soon after the establishment of ovulatory cycles, endometriosis-related dysmenorrhoea often starts in the early 20s, and is usually very severe, incapacitating and unresponsive to simple/mild analgesics or antiprostaglandins. If endometriosis is untreated, dysmenorrhoea progressively increases in duration, but severity tends to remain constant.

Dyspareunia

Another common symptom of endometriosis is deep dyspareunia resulting from stretching at intercourse of the involved pelvic tissues such as a fixed retroverted uterus, the uterosacral ligaments or rectovaginal septum; or pressure on an involved enlarged, often adherent, ovary. The presence of endometriotic tissue within these areas, however, is not always associated with dyspareunia; perhaps less than half of patients who are coitally active admit to this symptom when deposits are found in these areas. The pain continues for a variable time after intercourse, often as a dull ache. Typically, dyspareunia is exaggerated in the phase before menstruation commences. This pain is more severe in women with deep rectovaginal septum involvement and may result in complete apareunia.

Non-cyclic chronic pelvic pain

In approximately 30–50% of women with pelvic endometriosis, chronic pelvic pain (CPP) of varying severity, pattern and location is reported. Pelvic pain is arguably the symptom causing the most misery amongst endometriosis sufferers, and is more distressing than infertility. CPP, as with other forms of pain, often produces a serious long-term detrimental effect on the personality, and affects working ability and social and marital life. Possible causes include adhesions, ovarian cysts, peritoneal inflammatory reaction around implants, or involvement of bladder or bowel. Pain may be triggered by ovulation, bowel evacuation or micturition. Pain resulting from adhesions may be provoked or worsened by certain body positions or movements. A common feature of CPP is worsening before and during menstruation.

Menstrual irregularities

In 16% of women, the disease is associated with heavy and/or irregular periods or premenstrual spotting, the causes of which are undetermined.

Other symptoms associated with the menstrual cycle

Direct involvement of the bladder wall can result in haematuria and dysuria occurring at the time of menstruation. Invasion into the muscular coat of the descending colon and rectum (most commonly) can cause cyclical rectal bleeding and painful defaecation (dyschezia), whilst involvement of the small bowel or colon elsewhere may not present until a narrowing of the bowel lumen has occurred with complete or partial obstruction. Rarely, dysmenorrhoea may be associated with symptoms due to extrapelvic endometriosis (e.g. sciatica, groin pain), or cyclical haemoptysis or pneumoperitoneum with lung/pleural involvement. Other rare associations include bleeding, swelling and/or pain in surgical scars, umbilicus or episiotomy site affected by endometriosis.

Correlation of symptoms and severity of endometriosis

The frequencies of the more common symptoms in endometriosis patients are summarized in Table 33.3. Whilst the symptoms of dysmenorrhoea, dyspareunia and pelvic pain can occur with other gynaecological disorders, it is the combination, cyclical and menstrually related component of several symptoms which should alert the clinician to the potential underlying presence of endometriosis. Many women have delayed diagnosis of their condition, which may mean that it has progressed to a more extensive and potentially less reversible or curable stage at the time of diagnosis.

Table 33.3 Frequency of the more common symptoms in endometriosis patients

There appears to be little correlation between sites involved in endometriosis and symptoms. Various ‘types’ of symptoms can, however, be related to some degree to the system involved (see Table 33.2). However, these do not always correlate with the anatomy and type of pain innervation of the pelvis (for review, see MacLaverty and Shaw 1995).

One reason for the apparent lack of correlation between disease severity and symptom severity is that the classification systems for endometriosis thus developed have primarily been directed towards infertility prediction rather than pain symptom severity.

Deeply infiltrating endometriosis is very strongly associated with the presence and severity of pelvic pain. In addition, superficial non-pigmented endometriosis has the capacity to produce more prostaglandin F (PGF) than pigmented classic powder burn lesions. PGF is implicated in pain causation (Vernon et al 1986). Thus, in the early, less florid stages before it has become destructive and more easily recognized, endometriosis may be producing large quantities of PGF and hence possesses greater potential to increase the severity of pain. The type of pain may alter with disease progression, with constant pain and exacerbation at the menses initially in the disease, and pain later becoming continuous due to scar formation and organ fixity.

Conclusions

To date, it is not known how mild endometriosis (without tubo-ovarian disease or adhesions) causes infertility, but it is recognized that such patients have a reduced fecundity rate. Until the underlying cause (if any) is found and appropriate corrective therapies are available, such asymptomatic patients are best treated along the lines of unexplained infertile couples (see Chapters 20 and 22) with treatment options based on age and duration of infertility.

Symptomatic pointers

No single symptom is pathognomic of endometriosis, but severe dysmenorrhoea (pain sufficient to require time off work and/or to interfere with normal everyday activity) is highly predictive. Dyspareunia and pelvic pain are less predictive in the absence of severe dysmenorrhoea (Overton and Kennedy 1993). These gynaecological symptoms may, however, be of diagnostic help in the suspicion of endometriosis, which should be a differential diagnosis in any patient presenting with worsening dysmenorrhoea, pelvic pain and/or dyspareunia or with other cycle-associated symptoms relating specifically to the bowel, bladder or localized skin lesions (see Table 33.2 and Box 33.1). In endometriosis, the associated dysmenorrhoea extends to the pre- and postmenstrual phase, and is typically of secondary onset and progressive rather than being present from the onset of the menarche. In women presenting with pelvic pain, a history of whether or not this relates to the menstrual cycle is helpful in differentiating other aetiological causes of pain. In those with associated marked bowel symptoms, a trial of treatment for irritable bowel syndrome may be worthwhile before considering referral for diagnostic laparoscopy, although other pathologies may be present concurrently (see Box 33.2).

Clinical examination

Clinical abdominal examination may demonstrate local tender nodular lesions in a caesarean section or laparotomy scar, or at the umbilicus or other site of a laparoscopy port. Gynaecological speculum examination may visualize endometriotic lesions as clear red or bluish cysts or nodules in the vagina, most commonly in the posterior fornix, or on the cervix. This visual diagnosis cannot substitute for histological confirmation even if bleeding occurs from the lesions at the time of menstruation.

Pelvic examination often reveals induration of the uterosacral ligaments or nodules in the pouch of Douglas or rectovaginal septum. Involvement of the ovaries can lead to the development of endometriotic cysts which eventually become large enough to be palpable. There may be fixation of the uterus in retroversion, with the immobilization of the ovaries by adhesion formation, and tenderness, particularly when the patient is examined in the immediate premenstrual phase of the cycle. These clinical findings, whilst not specific to endometriosis, may add to the suspicion of the presence of the disease from the pointers obtained in the history.

Pelvic endometriosis

Pelvic endometriosis has been defined as endometriotic implants involving the peritoneum, anterior and posterial cul-de-sac and pelvic side walls, and the surfaces of the uterus, tubes and ovaries.

Diagnosis of pelvic endometriosis cannot be made with absolute certainty from symptoms or examination alone, and laparoscopic examination may be required to confirm the initial clinical diagnosis. The role of laparoscopy is to:

The laparoscopic features of pelvic endometriosis are many and varied, and it is clear that a carefully undertaken laparoscopy by an experienced surgeon is essential if cases are not to be missed at this diagnostic opportunity. Whenever there is any doubt, the need for biopsy confirmation is paramount. Careful recording of the laparoscopic findings is essential and photographic records are most helpful if patients are to be referred on for further management.

Morphology of the typical black lesions

The typical peritoneal endometriotic lesion is described as a ‘powder burn’ which results from tissue bleeding and retention of blood pigments, producing a brown–black discoloration of the tissue. In the early stages, these lesions may appear more pink, red and haemorrhagic, and develop into brown–black lesions with increasing time. Eventually, discoloration disappears altogether and a white plaque of old collagen is all that remains of the endometriotic implant (Figure 33.2).

Figure 33.2 Black deposits on the uterosacral ligament with the uterus in anteversion.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

Scarring in the peritoneum surrounding implants is also a typical finding. Apart from encapsulating an isolated implant, the scar tissue may deform the surrounding peritoneum, resulting in development of adhesions between adjacent pelvic structures. These adhesions are commonly found between the mobile pelvic structures, particularly the posterior leaf of the broad ligament and the ovary, and the dependent sigmoid colon and posterior aspect of the vagina and/or cervix.

Classification and morphology of subtle appearances

More recently, more subtle laparoscopic appearances have been reported which were confirmed on biopsy as being due to endometriosis (Donnez and Nisolle 1991). The subtle forms are more common and may be more active and more important than the puckered black lesions that represent the later stages of the disease. These other peritoneal lesions include red lesions and white lesions.

Red lesions

• Red flame-like lesions on the peritoneum, with the appearance of red vascular excrescences in the broad ligament and uterosacral ligaments, largely due to the presence of active endometriosis surrounded by stroma (Figure 33.3).

• Glandular excrescences which closely resemble the mucosa of the endometrium as seen at hysteroscopy; biopsy reveals the presence of numerous glandular elements (Figures 33.4 and 33.5).

Figure 33.3 Active endometriosis on the uterosacral ligament.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

Figure 33.4 Active endometriosis with glandular or stromal components in a biopsy specimen from a red lesion.

Figure 33.5 Vesicular implant of the ovarian fossa.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

White lesions

• White opacification of the peritoneum. These lesions contain an occasional retroperitoneal glandular structure, scanty stroma surrounded by fibrotic tissue and connective tissue (Figure 33.6).

• Yellow–brown peritoneal patches called ‘café-au-lait spots’, found in the cul-de-sac, broad ligament or over the bladder. Histologically, they are similar to findings of white opacification; the yellow–brown patches indicate the presence of haemosiderin.

• Circular peritoneal defects of the pelvic peritoneum, uterosacral ligaments or broad ligament. Serial section has demonstrated the presence of endometrial glands in approximately 50% of these structures (Figure 33.7).

Figure 33.6 Scarring neovascularization of the left uterosacral ligament.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

Figure 33.7 Peritoneal pouches near right uterosacral ligament associated with endometriosis.

Ovarian endometriosis

The ovary represents a unique site for implantation of endometrial fragments, as levels of gonadal steroids are several times higher than those in the general circulation or peritoneal cavity.

Superficial endometriosis

Superficial implants on the ovary resemble implants in other peritoneal sites. Comparable features are typical black, red or white lesions (Figure 33.8).

Figure 33.8 Superficial lesions on posterior aspect of ovary.

Endometrioma

The pathogenesis of the typical ovarian endometriotic cyst or endometrioma has now been clarified. It is a process originating from a free superficial implant which is in contact with the ovarian surface and is sealed off by adhesions (Figure 33.9). A pseudocyst is thus formed by accumulation of menstrual debris from shedding and bleeding of the small implant, resulting in fluid collection. Progressive invagination of the ovarian cortex occurs and the associated inflammatory reactive tissue progressively thickens the inverted cortex. Outgrowths through the endometrial epithelium, with or without stroma, extend over the surface or become embedded in the fibroreactive tissue covering the wall. This pathogenesis explains the typical features of an endometrium such as frequent location of the cyst, adhesions on the anterior side of the ovary opposing the posterior side of the parametrium or, when on the posterior aspect of the ovary, adhesions to the ovarian fossa. The contents of the cyst are, to a large extent, fluid which represents the debris from cyclical menstruation (Figures 33.10 and 33.11).

Figure 33.9 Diagrammatic representation of endometriosis formation, beginning on serosal surface and invaginating into cortex.

Figure 33.10 Left ovarian endometrioma.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

Figure 33.11 Enlarged left ovary containing a deep-seated endometrioma (left) and another ovary with superficial deposits on the ovarian capsule, in addition to others on the peritoneal surface in the pouch of Douglas (right).

There is usually a well-defined separation between the normal adjacent ovarian stroma and the cyst wall, but whilst the epithelial lining of the cyst may initially resemble the endometrium, with increasing time and size, pressure atrophy compresses the epithelium to a flat cuboidal pattern.

Ovarian endometriomas rarely occur in the adolescent, but incidence increases with age. Laparoscopic features of a typical endometrioma include ovarian cysts not greater than 12 cm in diameter, adhesions to the pelvic side wall and/or the posterior broad ligament, powder burns, minute red or blue spots with adjacent puckering on the surface, and the presence of the characteristic tarry, thick, chocolate-coloured fluid content (see Figure 33.10).

Extrapelvic endometriosis

Extrapelvic endometriosis is defined as endometriotic-like implants elsewhere in the peritoneal cavity or other body cavities. Extrapelvic endometriosis has been reported in virtually every organ, system and tissue, but far less frequently than pelvic endometriosis. Overall, the incidence of extrapelvic disease represents less than 12% of reported cases of endometriosis, and it appears that the frequency of occurrence decreases with the distance from the pelvis.

Involvement in surgical scars

Endometriosis in surgical scars has been reported in the umbilicus or other port sites following laparoscopy, in abdominal incisions following gynaecological surgery and caesarean section, and in the perineum within episiotomy scars following childbirth (Figure 33.12). Such patients present with a painful, palpable swelling, usually more symptomatic at the time of menstruation. Occasionally, some women report discharge or cyclical bleeding occurring perimenstrually from the lesions. While medical treatment will control the symptoms with effective suppression of menstruation, surgical excision of the nodule will normally be necessary in the long term.

Figure 33.12 Endometriosis in episiotomy scar. The patient presented with cyclic, tender swelling in the perineum.

Non-invasive methods of diagnosis

It is an unsatisfactory situation that in order to diagnose endometriosis with certainty, an invasive, albeit minor, surgical procedure in the form of laparoscopy needs to be performed. This can readily be justified for making the initial diagnosis, but if the nature of the disease is of recurrence for the majority of patients throughout their reproductive life, this may involve repeat laparoscopies on many occasions if one is to be certain that the disease process has returned. Attempts have therefore been made to provide a non-invasive test which is highly sensitive and specific for endometriosis. Currently, such a test eludes investigators, although a number of adjunctive non-invasive tests may be contributory in the management of patients.

Imaging techniques

Ultrasound

Ultrasound examination of the pelvis may be useful in delineating the presence and aetiology of ovarian cystic structures. The characteristic pictures on ultrasound are different when there is a large proportion of blood, such as haemorrhagic corpus luteum cysts or endometriomas, which in a minority of cases may be echo free. However, the walls of an endometrioma are irregular as opposed to the smooth wall of the simple ovarian cyst. The most common pattern is for the chocolate cyst to contain low-level echoes or lumps of dense high-level echoes representing blood clots. The picture may sometimes be confused if there are several cysts in different phases of evolution (see Figure 33.13).

Figure 33.13 Transvaginal ultrasound scan showing the typical ground-glass appearance of endometrioma.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

Transrectal ultrasound may be of value before surgery in patients in whom rectal/rectovaginal septum involvement is suspected. This method permits measurement of the distance between the lesion and anal verge, as well as assessment of extrinsic compression and lesions in the rectal submucosal layer (Abrão et al 2004). This method is limited to evaluating the rectosigmoid and retrocervical region. It is advisable to undertake such examinations 1 h after a simple rectal enema.

Ultrasound may also be useful to identify hypoechogenic nodules in the bladder wall when bladder involvement is suspected, most often in the vesico-uterine fold.

Analgesics

Simple analgesics (e.g. paracetamol, aspirin) can be used but have often been tried and failed prior to referral to a specialist gynaecologist. They are helpful to a degree for the mild-to-moderate pain of endometriosis. A clinical feature in many women with the disease, as it progresses, is the failure of simple analgesics to work, and more potent agents (Tramadol, Dicolfenac etc.) may be required.

Prostaglandin synthetase inhibitors

An association with prostaglandin release and dysmenorrhoea has long been established. One might therefore expect that prostaglandin synthetase inhibitors (PGSIs) might have a beneficial effect in treating the symptoms of endometriosis. PGSIs are a heterogeneous group of non-steroidal inflammatory agents which act mainly by inhibiting the production of prostaglandins, although some (fenamates) also antagonize prostaglandins at the target level. These agents are perhaps beneficial in the early stages of initial or recurrent disease, but when symptoms become more severe, they are usually inadequate by themselves to control symptomatology.

There are surprisingly few data on the evaluation of the effectiveness of analgesics or PGSIs in treating endometriosis-associated pain.

Gestagen and antigestagen treatment

A state of pseudopregnancy can be induced effectively by the continuous administration of progestogenic preparations. The progestogens used are derivatives of progesterone (dydogesterone or medroxyprogesterone acetate) or 19-nor-testosterone (norethisterone, norethisterone acetate, norgestrel, ethynodrel and lynoestrenol).

The use of progestogens induces a hyperprogestogenic/hypo-oestrogenic state. Treatments are available orally or injected as a depot formulation, and are administered for 6–9 months. The results achieved appear to be comparable to those achieved with combined oral oestrogen–progestogen preparations in the past. The side-effects most commonly seen with progestogen usage include breakthrough bleeding, weight gain, abdominal bloating, oedema, acne and mood changes.

The adverse effects of some progestogens on circulating levels of low- and high-density lipoproteins may determine the choice of progestogen if long-term administration is planned.

The oral progestogens used most commonly to attempt to induce amenorrhoea are:

Long-acting depot preparations of progestogens (Depo-Provera 150 mg, 3 monthly) can be used. However, the author’s personal experience has been that in order to avoid the initial problems (e.g. erratic/irregular vaginal bleeding), this may be best commenced once amenorrhoea has been achieved with other agents (e.g. GnRH analogues) for a few months. Depo-Provera has been shown to be as effective as the combined oral contraceptive pill (COCP) or danazol in reducing endometriosis-associated pain (Vercellini et al 1996).

Levonorgestrel intrauterine system

The levonorgestrel intrauterine system (LNG-IUS) was introduced as a long-acting contraceptive coil method, but its utility as a treatment option in gynaecology has been expanded into the treatment of menorrhagia due to dysfunction (unexplained) causes (see Chapter 31) and more recently in the treatment of endometriosis.

The steady low level of LNG achieved in the peripheral circulation appears to have a direct effect on the growth of endometriotic deposits through peritoneal fluid. The suppression of menstruation, or marked reduction of flow, may also be beneficial in reducing the amount of retrograde menstrual regurgitation, which may help to prevent new disease induction.

Effectiveness data come from two randomized controlled trials. In a study comparing LNG-IUS with expectant management, significantly lower pain scores were achieved in the LNG-IUS women at 12 months (Vercellini et al 2003). In the second trial, LNG-IUS was compared with GnRH analogue; after 6 months of treatment, both treatments were equally effective in reducing pain scores (Petta et al 2005).

Larger trials are required, along with long-term data, to enable clinicians to determine the types of disease and subjects with endometriosis in which the LNG-IUS may be of benefit.

Combined oral contraceptive pill

The COCP reduces pain associated with endometriosis, is well tolerated and can be continued long term for the control of symptoms in healthy women without risk factors. One of a number of ‘high-dose’ COCPs may be administered, and regimes often utilize COCPs prescribed continuously for three cycles to reduce the frequency of menstruation. If breakthrough bleeding occurs before planned interval bleeding, changing to another preparation with a higher progestogenic content is advocated.

Side-effects such as weight gain, headaches, breast enlargement and/or tenderness, nausea and depression may occur. The risk of thromboembolism is increased, and a personal previous history or family history of venous thromboembolism may involve screening for risk factors, including factor V Leiden polymorphism, prior to administration.

Gonadotrophin-releasing hormone agonists

Surgical castration is known to be an effective therapy for severe endometriosis. Thus, the possibility of inducing a reversible medical castration with the continued administration of GnRH agonists has been investigated as an alternative therapy in endometriosis. Modification of the native GnRH molecule with substitution, particularly in positions 6 and 10, with alternative amino acids produces agonistic analogues with a reduced susceptibility to degradation and hence a prolonged therapeutic half-life (Figure 33.14). Continued administration of these analogues induces pituitary gonadotrophin desensitization via downregulation of GnRH receptors and an eventual state of hypogonadotrophic hypogonadism. Reduced gonadotrophic stimulation of the ovaries leads to cessation of follicular growth and reduction in ovarian steroidogenesis, with circulating 17β-oestradiol levels falling to those observed in the postmenopausal range (typically less than 100 pmol/l).

Figure 33.14 Amino acid sequence of native luteinizing-hormone-releasing hormone (LHRH) and some of the agonistic gonadotrophin-releasing hormone (GnRH) analogues used in the treatment of endometriosis.

A large amount of data has now appeared in the literature from both controlled and randomized comparative trials of GnRH analogues and danazol (for review, see Shaw 1995). These trials have all confirmed the value of GnRH analogues for the treatment of endometriosis. Rapid and effective symptomatic relief is achieved with these agents, as well as a marked degree of resolution of the endometrial deposits in the majority of patients. However, for both symptomatic relief and the resolution of endometrial deposits, there is essentially no significant difference in comparative trials between GnRH analogues and danazol. However, patient acceptability and the profile of side-effects may be slightly in favour of GnRH analogues (Matta and Shaw 1987, Henzl et al 1988).

Side-effects of GnRH analogues include those which are predictable from induction of a pseudomenopause. These include hot flushes (in virtually all patients), headaches and, less commonly, atrophic vaginitis, vaginal dryness and reduced libido.

Dosage varies depending on the analogue used and its formulation, but regimens include: nafarelin 200 µg twice daily intranasally, buserelin 300–400 µg three times daily intranasally, goserelin 3.6 mg subcutaneous depot monthly, triptorelin 3.0 mg monthly, and leuprorelin 3.75 mg intramuscular depot monthly.

Metabolic side-effects include (as in the menopause) increased excretion of urinary calcium. Over a 6-month period, there is a 3–5% loss in the vertebral trabecular bone density of the lumbar spine as assessed by dual energy X-ray absorptiometry. In most patients, the bone density changes induced following a 6-month course of therapy with GnRH analogues are reversed 6 months after return of ovarian function (Matta et al 1987, Henzl et al 1988). However, the implications of such changes in calcium homeostasis with prolonged and repetitive treatment with GnRH analogues are being further investigated. This has led to the development of protective ‘add-back’ regimens which reduce the symptomatic effects of the GnRH-agonist-induced hypo-oestrogenism, particularly the frequency of hot flushes and bone loss, but do not result in reduced therapeutic effectiveness on symptom relief or implant resolution. A recent meta-analysis of 15 studies assessing GnRH agonists with add-back with oestrogen and progestogen showed protection to the lumbar spine for up to 12 months following cessation of treatment (Sagsveen et al 2003).

A new series of GnRH antagonists are currently being developed, and these peptides contain multiple and complex substitutions of the GnRH molecule. There is little evidence on long-term use of GnRH antagonists in the treatment of endometriosis to date, and their structural complexity and costs may make substitution of GnRH antagonists for the current widely used GnRH agonists unlikely. However, orally administered non-peptide GnRH receptor antagonists are being developed and may present alternative therapies in the future.

Danazol

Danazol is an isoxazol derivate of 17-α-ethinyl testosterone. Due to its base structure, it has both androgenic and anabolic properties. Danazol was one of the first approved medical treatments for endometriosis. Its mechanism of action is complex and includes suppression of the hypothalamic–pituitary axis with interference in pulsatile gonadotrophin secretion and inhibition of the midcycle gonadotrophin surge, but with no change in basal gonadotrophin levels. It achieves direct inhibition of ovarian steroidogenesis by inhibiting several enzymatic processes and by competitive blockage of androgen, oestrogen and progesterone receptors in the endometrium. An increase in free testosterone occurs because of a reduction in sex-hormone-binding globulin, and this explains many of danazol’s androgenic side-effects. The increase in free testosterone may also contribute to its direct action in inducing endometrial atrophy. The degree of endocrine changes described above is dose related.

In the treatment of endometriosis, danazol is administered in a dose range of between 400 and 800 mg daily, titrated to endeavour to induce amenorrhoea. In the case of mild-to-moderate endometriosis, there is highly effective symptomatic improvement in over 85% of cases.

Objective resolution of endometriotic lesions has been observed at post-treatment laparoscopic evaluation in between 70% and 95% of patients, depending upon the stage of the disease (Barbieri et al 1982). However, recurrence rates of up to 40% have been reported in the 36 months after completion of a course of danazol.

Danazol therapy should be commenced in the early follicular phase of the menstrual cycle. It is recommended that the patient should use additional barrier methods of contraception in order to avoid the drug being administered during early pregnancy, where continued use could lead to androgenization of a developing female fetus. The drug dosage should be related to the patient’s clinical staging, response and severity of side-effects, starting with a dose of 400 mg/day in mild disease and 600–800 mg/day in moderate-to-severe cases for a recommended treatment course of at least 6 months.

Danazol is associated with side-effects related to its androgenic and anabolic properties. These include weight gain, acne, oily skin, fluid retention, muscle cramps, hot flushes, depression and mood changes. Less commonly, hirsutism, skin rash and voice deepening are noted. It is recommended that patients should discontinue treatment immediately if they develop hirsutism, a skin rash or deepening of the voice.

Metabolic side-effects include elevation of low-density lipoproteins, and reduction of high-density lipoproteins and cholesterol concentrations. In addition, changes in liver enzymes are noted, and danazol is contraindicated in patients with liver disease.

Gestrinone

Gestrinone is a synthetic trienic 19-norsteroid (13-ethyl-17-α-ethinyl-17-hydroxy-gona-4,o,Il-triene-3-one). It has been shown in clinical trials to be another effective clinical treatment for endometriosis (Thomas and Cooke 1987). The drug exhibits mild androgenic and antigonadotrophic properties. The combined effect is to induce progressive endometrial atrophy. Gestrinone has a high binding affinity for progesterone receptors; it also binds to androgen receptors but not to oestrogen receptors. The combined endocrine effect of gestrinone therapy is similar to that of danazol in that the midcycle gonadotrophin surge is abolished, although basal gonadotrophin levels are not significantly reduced, together with inhibition of ovarian steroidogenesis and reduction of sex-hormone-binding globulin levels. Gestrinone has a prolonged half-life and may be administered orally at a dosage of 2.5–5.0 mg twice weekly for a period of 6–9 months in patients with endometriosis. This dosage schedule effectively induces endometrial atrophy, with 85–90% of patients becoming amenorrhoeic within 2 months.

Gestrinone compares favourably with danazol in terms of both symptomatic relief and resolution of endometrial deposits (Mettler and Semm 1984).

The side-effects, occurring in up to 50% of patients, include weight gain, breakthrough bleeding, reduced breast size, muscle cramps and, uncommonly, hirsutism, voice change and hoarseness.

Aromatase inhibitors

Aromatase P-450 is the key enzyme for oestrogen biosynthesis, and catalyses the conversion of andostenedione and testosterone to oestrone and oestradiol. Aromatase activity is expressed inappropriately in endometriotic deposits and their eutopic endometrium, but not in the endometrium of normal women. Prostaglandin E₂ is a potent inducer of aromatase activity in endometriotic cells, and hence there is a link between repeated proliferation and inflammation within endometriosis deposits.

Limited data have been published on the use of aromatase inhibitors in endometriosis. A meta-analysis of 40 women from seven published case studies utilizing aromatase inhibitors in combination with progestogens, COCP or GnRH-A reported reduced mean pain scores and lesion size, and improved quality-of-life scores (Nawathe et al 2008). More data are needed to establish the efficacy and safety of aromatase inhibitors, and which combination of drugs produces the best results.

Other drug therapies tried or in development

A number of potential new drug therapies to treat endometriosis have been postulated, investigated in animals or are under development. These include progesterone antagonists, selective oestrogen receptor modulators and statins. However, scant, often only research data exist, and further data or modification of regimens to reduce side-effects would be necessary before they become clinically viable therapies.

In addition, research is underway to evaluate selective progesterone receptor modulators, selective oestrogen receptor β-agonists, angiogenesis inhibitors and immunomodulators/inflammatory modulators. It will be some considerable time before it is known if any of these approaches prove to be effective and tolerable as therapeutic options in the treatment of endometriosis.

Conservative surgery

Endometriotic deposits may be excised, destroyed by electrocautery, or evaporated utilizing carbon dioxide or KTP/YAG lasers or argon beam.

With the increasingly widespread availability of laparoscopic expertise, improved instrumentation and experience of laser technology, minimal access surgery is becoming a more popular treatment option. There have been few appropriately conducted randomized trials, but one small double-blind placebo-controlled study measured pain relief following laser ablation and/or laparoscopic uterosacral nerve ablation or placebo (no treatment). At 6 month follow-up, 53% of those treated with laser compared with only 23% from the placebo diagnostic laparoscopy group had improvements in symptoms (Sutton et al 1994). It was of interest that in minimal disease, only 38% of women had a reduction in pain. Therefore, this approach appeared to be more effective in reducing pain symptoms in women with more severe disease.

Sutton et al (1997) published the results of a longer term follow-up of this cohort of patients. Sadly, 1 year after the initial treatment, 44% had recurrence of pain requiring additional treatment. The reasons for failure of the surgical approach may result from missing lesions, incomplete destruction and, of course, recurrence of the disease.

An alternative approach to ablation of lesions is excision. Advocates of this approach argue that excision is the only way to ensure complete treatment because it may be difficult to determine the depth of the implant. Local excision can achieve good results in terms of pain reduction — 67% improvement up to 12 months (Wykes et al 2006) — but another study reported a high reoperation rate with longer term follow-up of 46% at 5 years and 55% at 7 years (Shakiba et al 2008) (see Figures 33.15 and 33.16).

Figure 33.15 Left uterosacral nodule.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

Figure 33.16 Excision of the uterosacral ligaments and bilateral uterosacral nodules.

Source: Overton C, Davis C, McMillan L, Shaw RW 2007 An Atlas of Endometriosis, 3rd edn. Informa Healthcare, London.

Laparoscopic uterosacral nerve ablation

The uterosacral ligaments are a commonly affected site in patients suffering with endometriosis, and infiltration of endometriotic deposits results in invasion, inflammation and fibrosis of the anterior extension of the inferior hypogastric nerve, the uterovaginal plexus (or Lee-Frankenhauser plexus). Ablation of the uterosacral ligaments, forming two small craters, can be performed at the time of laparoscopy. The risks of the procedure are haemorrhage from a vessel within the uterosacral ligaments and damage to the ureter, which needs to be identified before laser treatment commences.

In a double-blind randomized controlled study, the addition of laparoscopic uterosacral nerve ablation to laparoscopic laser vaporization of endometriotic lesions alone was not found to improve pelvic pain responses (Sutton et al 2001). This procedure should not be performed if the uterosacral ligaments have a normal appearance, whilst excision of deep infiltrating lesions on the uterosacral ligament seems to be beneficial.

Radical surgery: hysterectomy and oophorectomy

Radical surgery is reserved for those patients with severe symptoms, where there is no desired fertility potential and especially when other forms of treatment have failed. Total abdominal hysterectomy and bilateral salpingo-oophorectomy are performed along with resection of any endometriotic lesions as completely as possible. As the majority of these patients are relatively young, hormone replacement therapy should be commenced but kept to a minimum to control oestrogen-deficiency symptoms, as a small percentage of those patients may develop a recurrence of endometriosis when on such oestrogen replacement.

Combined oestrogen–testosterone implants may minimize the risk of recurrence as well as offering the beneficial effects of the androgens in maintaining libido in young women who are sexually active. However, no data exist from randomized trials to define if one particular hormone replacement therapy regimen is superior to others.

Surgical treatment of endometriomas

The definitive treatment of the typical endometrioma is the surgical release of the adhesions and fibrosis at the site of invagination, and the eversion of the invaginated cortex. Simply puncturing and draining the endometrioma, whether this is followed by GnRH agonist therapy or not, has no beneficial effects in the long term (Vercellini et al 1992). Medical treatment is highly effective for the destruction of active implants located on the surface of the normal ovarian cortex. However, when a definite endometrioma is present, surgery is necessary. This can be performed laparoscopically for smaller endometriomas using laser destruction. With endometriomas larger than 3 cm in diameter, treatment may be facilitated to enable laparoscopic surgery if, following initial drainage, patients are pretreated for 3 months with a GnRH agonist prior to laser ablation (Donnez et al 1990).

On the other hand, fibrotic larger endometriomas have a thickened capsule which is more likely to be removed effectively by excisional techniques.

In many instances, however, because of other associated extensive adhesions and fixity of ovaries on to other structures, a laparotomy rather than a laparoscopy may be necessary.

Whatever the surgical approach, be it minimal access or open laparotomy, if dense and extensive adhesions are present at the time of original surgery, it is likely that such patients will have recurrence of adhesions with attendant problems of fixity of the ovary following such approaches (Shaw et al 2001).