Key words
endometriosis - laparoscopy - reproductive medicine - health care
Schlüsselwörter
Endometriose - Laparoskopie - Reproduktionsmedizin - Gesundheitswesen
1 Background
In this guideline, a standard is recommended for the diagnosis and treatment of endometriosis
on the basis of the previously published scientific knowledge and of the experience
of the authors. Doctors providing care for patients with endometriosis represent the
target group for this guideline.
The recommendations are based on an analysis of the scientific literature (PubMed,
MEDLINE search, Cochrane Library), although only a limited number of prospective,
randomized studies are available on the diagnosis and treatment of endometriosis.
The recommendations and publications of the following professional associations were
also taken into consideration:
2 Introduction
2.1 Definition and epidemiology
Core statements:
-
Endometriosis is defined as the presence of endometrium-like groups of cells outside
the uterine cavity.
-
The cardinal symptom is pelvic pain, and infertility is common.
Endometriosis is one of the most common gynecological diseases. It occurs predominantly
after sexual maturity has been reached and is considered to be estrogen-dependent.
In one study, adolescents in the 10- to 15-year-old age group represented 0.05 % and
in the 15- to 20-year-old age group 1.93 % of all women with endometriosis. Postmenopausal
women accounted for 2.55 % of the cases [78]. Endometriosis is a cause of significant morbidity [5], [68], [172].
Reliable information on frequency is lacking, and there are significant fluctuations
in the prevalence rates quoted in the literature. It is estimated that approx. 40 000
new cases occur in Germany each year. Around 20 000 women are admitted for hospital
treatment for endometriosis each year in Germany [78]. The economic impact is considerable in terms of medical cost and reduced work productivity.
Despite this, the disease is under-represented in clinical and basic scientific research
[168].
The dilemma of endometriosis is caused partly by the long interval between the appearance
of the first symptoms and the correct diagnosis – 10 years on average in Austria and
Germany [91] – and partly by the repeated operations in chronic forms of the disease.
Although endometriosis is a histopathologically benign disease, it can spread to other
organs as a result of infiltrative growth and require extensive surgery [189].
2.2 Etiology, pathology and staging
Core statement:
The etiology and pathogenesis of endometriosis are still not fully understood. There
is, therefore, no known causal treatment at present.
Recommendation:
All known staging systems have their limitations. For the purpose of international
comparability, the rASRM staging system should be used, with the addition of the ENZIAN
classification in deep infiltrating endometriosis.
Various theories on the etiology and pathology of endometriosis have been presented
in the literature: implantation theory [164], [165], celomic metaplasia theory [126], archimetra or “tissue injury and repair” concept [113], [114].
The most widely used classification is that of the American Society for Reproductive
Medicine (the “rASRM score”, [11]). This rASRM score shows only a weak correlation
with the cardinal symptoms of pain and infertility [72], [194]. The description of retroperitoneal and deep infiltrating growth forms is also inadequate
with this system. The Endometriosis Research Foundation has attempted to overcome
this shortcoming by creating an appropriate classification – the ENZIAN classification
[77], [79], [80], [157], [186]. Like the rASRM score, the ENZIAN classification is also morphologically descriptive.
At present, no data exist showing whether the ENZIAN classification correlates with
symptoms such as pain and infertility. The traditional division into external and
internal genital endometriosis and extragenital endometriosis [9] has proven useful in routine clinical practice; it takes into account the concept
of a single disease entity.
In decreasing order of frequency, the following are involved: pelvic peritoneum, ovaries,
uterosacral ligaments, rectovaginal septum/vaginal fornix, and extragenital sites
(e.g., rectosigmoid colon and urinary bladder).
The incidence of involvement of the uterus (adenomyosis) and tubes is not entirely
clear. The diaphragmatic peritoneum [137], [155], the vermiform appendix [71] and the umbilicus [197] are rare but typical extragenital sites. Endometriosis also occurs in surgical scars
following hysterectomy, cesarean section, episiotomy, and perineal lacerations [19], [62], [144], [167]. It is debated that this may be caused by the mechanical transfer of endometrial
particles. Manifestations in the spleen, lungs, kidneys, brain or skeleton are rare.
Patient information – Causes of endometriosis
The causes of the development of endometriosis have not yet been scientifically proven.
No causal treatment options are, therefore, available at present which might enable
endometriosis to be eliminated completely or cured. There is also no treatment available
that prevents endometriosis from developing in the first place.
Endometriosis and malignancy
Core statements:
-
In very rare cases, malignancy may arise from endometriosis – usually ovarian cancer.
-
An association with the occurrence of other, non-gynecological malignancies can also
be found in the literature. The clinical significance of this observation is unclear.
Risk of malignant diseases in women with endometriosis
Even though there is no statistically detectable increase in the risk of cancer for
women with endometriosis in general [122], [181], an association has been described between the existence of endometriosis and certain
malignancies such as endocrine tumors, ovarian cancer, renal cell carcinoma, brain
tumors, malignant melanoma, non-Hodgkin lymphomas and breast cancer [28], [82], [122], [136], [139], [148], [198]. The standardized incidence ratio (SIR) is stated as, for example, 1.38 for endocrine
tumors, 1.37 for ovarian cancer and 1.08 for breast cancer [122]. The SIR might be even higher in women with primary infertility, endometriosis and
one of the aforementioned malignancies [27]. The validity of these data and their clinical significance are unclear.
Endometriosis-associated malignancies
Malignant tumors may arise from endometriosis. Ovarian cancer accounts for around
80 % and extragonadal tumors for 20 % of these cases [187], [199], with the positive correlation persisting even if it was many years previously that
the woman had the endometriosis [148]. Endometriosis is considered to be a risk factor that can accelerate the development
of ovarian cancer by 5 years [12]. According to one study, the overall risk is approx. 2.5 % [190]. Histologically, the tumors are mainly of the endometrioid (OR 3.05) or clear cell
(OR 2.04) type, although a correlation has been found recently between endometriosis
and well differentiated (G1) serous carcinomas (OR 2.11) [148]. The association between poorly differentiated (high-grade) serous and mucinous
ovarian carcinomas or borderline ovarian tumors is not statistically significant [148]. Other histologic entities occur (endometrial stromal sarcoma, mixed tumors, etc.)
[200]. Furthermore, an ovarian endometrioma diameter of ≥ 9 cm, a postmenopausal situation
[106] and a hyperestrogenic state [206] are reported to be independent risk factors (single center data). In the Swedish
Hospital Discharge Registry of 2004, the presence of endometrial cysts in women between
10 and 29 years of age was defined as an additional risk factor for the subsequent
development of ovarian cancer [25]. Ovulation inhibitors, births, tubal sterilization or hysterectomy might reduce
the risk, on the other hand [128]. Extragonadal endometriosis-associated carcinomas have virtually been described
in almost all tissues in which endometriosis occurs [121].
Summary
On the basis of the described incidence rates and risk factors, the possibility of
endometriosis-associated malignant disease should be included in considerations relating
to differential diagnosis, and patients should be informed about this accordingly.
At the same time, it is important to exercise prudence and to keep a sense of proportion
when confronting endometriosis patients with these statements.
Patient information – Endometriosis and malignancy
Even if women with endometriosis are not generally at increased risk of malignant
disease, some malignant diseases may occur more frequently than in women who do not
have endometriosis. The work-up for and treatment of endometriosis should, therefore,
take this fact and the individual situation of the woman concerned into account. Specific
additional investigations may thus be required in individual cases.
3 Diagnosis and Treatment of Endometriosis
3 Diagnosis and Treatment of Endometriosis
Core statements:
-
Indications for endoscopic diagnosis and treatment in endometriosis are as follows:
-
Surgical removal of the lesions is considered the “gold standard” for symptom control
[1], [50], [67].
Recommendation:
In general, the diagnosis of endometriosis is to be established histologically. Hence,
laparoscopy is essential for the diagnostic work-up [202].
3.1 General remarks
Some of the women affected are asymptomatic. Furthermore, the disease stage does not
correlate with the severity of the symptoms [70], [161]. The determination of CA-125 levels is not helpful either for diagnosis or follow-up
and is not recommended (see section 3.3.1, [131]). In some cases, it is difficult to prove whether a causal relationship actually
exists between endometriosis and certain symptoms. Asymptomatic endometriosis in a
patient who does not wish to become pregnant is not generally an indication for surgical
or medical intervention. There are exceptions to this, e.g., endometriosis-induced
ureteral stenosis with hydronephrosis (absolute indication). Almost all women with
symptomatic endometriosis suffer from dysmenorrhea. If this cardinal symptom is absent, other
causes of pelvic pain must be considered in the differential diagnosis [173], [174].
For the sake of clarity, the different forms of endometriosis are discussed separately.
Nevertheless, they are often combined [188].
Patient information – General notes on diagnosis and treatment
In the presence of suspected endometriosis, a histologic assessment should be performed.
As a general rule, laparoscopy is necessary for this. Persistent pain, desire to conceive
and/or functional impairment of an affected organ (e.g. ovaries, bowel or ureter)
are reasons for the surgical and/or pharmacological treatment of endometriosis. Conversely,
it follows that a woman who has endometriosis but does not have any symptoms, does
not wish to conceive and does not exhibit any organ damage, does not need to be treated,
although it is always important to consider the patientʼs individual situation.
3.2 Peritoneal endometriosis
Core statements:
Recommendation:
Following medical suppression of the ovarian function, endometriotic implants may
undergo regression. To reduce endometriosis-associated symptoms, progestins, oral
contraceptives or GnRH analogs can be used in order to induce therapeutic amenorrhea.
3.2.1 Morphology and symptoms
In peritoneal endometriosis, a distinction is made between red, white and black lesions
[11] and/or between pigmented and non-pigmented (atypical) lesions [95], [138]. The red and non-pigmented lesions are seen as early manifestations of endometriosis.
They are considered to be particularly active. In terms of response to hormone therapy,
peritoneal endometriosis appears to differ from ovarian and deep infiltrating endometriosis
[138]. It is not known, however, whether the different forms of peritoneal endometriosis
behave differently in relation to pain, fertility and course of the disease [75]. Patients with pronounced symptoms prior to surgery are at higher risk of recurrence
than patients who do not feel much pain [156]. The lifetime risk of endometriosis recurrence depends on the age at initial diagnosis
and is 1.75-fold higher for 20- to 29-year-old than for 30- to 39-year-old patients
[171]. Early diagnosis of endometriosis, including in adolescent girls, might be of significance
in terms of the subsequent course of the disease and the maintenance of fertility
[4], [204].
3.2.2 Diagnosis
Following a detailed past medical history-taking and vaginal/rectal examination, the
key measure for diagnosing peritoneal endometriosis is laparoscopy with histologic
confirmation [67]. Transvaginal ultrasonography or MRI are equally irrelevant to the detection of
peritoneal implants, although the former serves to rule out ovarian endometriosis
[132], and the latter may provide additional information where deep infiltrating endometriosis
is present at the same time [105].
3.2.3 Treatment
Surgical treatment
Laparoscopic removal of the lesions is the primary therapeutic objective. This has
been shown to reduce the pain [93]. Whether the methods available (coagulation, vaporization, excision) are equivalent
is unclear [81]. Additional LUNA (laparoscopic uterine nerve ablation) does not lead to any improvement
in outcome in patients with minimal to moderate endometriosis who have pain [196]. It has not been proven whether postoperative pharmacological suppression of ovarian
function is successful in improving the effect of surgery or maintaining it for longer
[64].
One option for reducing persistent pain after surgery is the insertion of a levonorgestrel-releasing
IUD [2].
Primary medical treatment
Suppression of ovarian function produces regressive changes in endometriotic implants.
A reduction in endometriosis-associated symptoms can be achieved equally with progestins,
oral contraceptives (continuous) or GnRH analogs [29], [73], [211], while GnRH analogs were more effective for dysmenorrhea and dyspareunia in some
studies. Differences exist in terms of the adverse effect profiles and costs, however
[30], [47], [84], [193]. In two current, prospective and randomized studies, continuous oral administration
of a progestin (dienogest) has been shown to have the same efficacy as a GnRH analog
in endometriosis-associated pain, while dienogest offered advantages for the patient
in terms of clinical tolerability [74], [180]. Long-term data show a sustained clinical effect continuing beyond the period of
administration [151].
When administered over a more prolonged period of time, GnRH analogs should be administered
concomitantly with appropriate protective add-back medication because of the potential
effects of estrogen deficiency. The duration of treatment with GnRH analogs is 6 months
in patients with pain. Although a 3-month treatment period is just as effective, it
is associated with a shorter recurrence-free interval [83]. No data are available on the benefit of extended GnRH-a therapy. According to the
findings of one prospective study, treatment with dienogest as maintenance therapy
after GnRH-a was effective in maintaining the GnRH-a-induced effect for at least 12
months [103]. Although non-steroidal and other anti-inflammatory drugs are used frequently in
routine clinical practice, there is no evidence at present that they have a positive
influence on the specific symptoms associated with endometriosis [10].
3.3 Ovarian endometriomas
Core statement:
The diagnosis of ovarian endometriomas is primarily made by transvaginal ultrasound.
Recommendations:
-
For primary treatment of ovarian endometriomas, the cyst wall should be removed surgically.
Fenestration alone is insufficient.
-
Hormonal drug treatment alone is neither effective in eliminating an ovarian endometrioma
and thus to replace its surgical removal, nor in compensating for incomplete surgical
removal. Therefore, it is not recommended.
3.3.1 Diagnosis
In 20–50 % of all women with endometriosis, the ovaries are affected [89]. The preoperative work-up is based on the clinical examination and transvaginal
ultrasound, with ovarian endometrioma often exhibiting a typical echo texture [88]. However, sonographically complex ovarian masses with a heterogeneous appearance
are also found, which makes it difficult to distinguish between functional cysts on
the one hand and dermoid cysts, cystomas or ovarian cancer on the other in individual
cases [109] ([Table 1]). In the case of planned laparoscopic procedures in the presence of unclear ovarian
findings, reference is made to the relevant S1 Guideline of the German Society for
Obstetrics and Gynecology (Guideline: laparoscopic surgery for ovarian tumors, AWMF
no. 015-003). Any unclear ovarian mass should be evaluated histologically.
Table 1 Ultrasound appearance of ovarian endometrioma in premenopausal women (modified according
to [88], [191]).
|
Appearance:
|
heterogeneous
|
|
Size:
|
up to 15 cm
|
|
Borders:
|
smooth
|
|
Wall thickness:
|
increased
|
|
Echogenicity:
|
not anechogenic (hypo- to hyperechogenic)
|
|
Internal echoes:
|
fine, uniformly distributed
|
|
Further features:
|
one or more compartments
|
|
uni- or bilateral
|
|
The same characteristics are associated with a higher risk of malignancy in postmenopausal
women.
|
If there is pain, additional deep infiltrating endometriosis is probably present [40] which must be taken into consideration during the clinical examination.
Determination of tumor markers
The CA-125 value is often assessed in the differential diagnostic work-up of complex
ovarian masses. As the CA-125 value is commonly elevated in endometriosis patients,
however, it is of no relevance in terms of the differential diagnosis (Guideline:
laparoscopic surgery for ovarian tumors, AWMF no. 015-003). It is not sufficiently
specific. Therefore, its determination for the evaluation of suspected endometriosis
is not recommended in the clinical routine. In the course of the disease (e.g., in
a suspected recurrence), the clinical situation is the decisive factor rather than
the CA-125 level. The same applies at present to serum levels of human epididymis
secretory protein 4 (HE4) [112], [207].
3.3.2 Treatment
The most effective treatment for ovarian endometriomas is their surgical removal.
The method of choice for this is surgical laparoscopy [32]. According to a meta-analysis, ovary-sparing removal (extraction) of the cyst wall
is superior overall to thermal destruction using a high-frequency current, laser vaporization
or argon plasma coagulation in terms of pain symptoms and recurrence and pregnancy
rates [76]. Whether this recommendation should apply only to endometriomas with a diameter
of > 4 cm is a moot point [85], [100]. The problem of the potential loss of oocytes following the excision of recurrent
endometriomas in infertility patients resulting in the procedure not being performed
prior to assisted reproduction (but therefore also in no histologic confirmation being
obtained) in the case of smaller endometriomas, will be examined later in detail in
section 4.3. The experience of the surgeon may have an influence on this oocyte loss
[205].
The opening and drainage of the cyst capsule of the endometrioma cannot be recommended
as a surgical procedure alone because 80 % of patients receiving this treatment suffer
a recurrence within six months [7], [162]. This high recurrence rate cannot be reduced by subsequent treatment with GnRH analogs
[192].
Medical (hormonal) treatment for ovarian endometriomas alone is not sufficient and
is not recommended. Pre-operative administration of GnRH analogs may lead to a decrease
in the size of the endometrioma. Whether this results in surgical benefits or a reduction
in recurrence rates is the subject of controversy in the literature [53], [134]. Postoperative GnRH analogs do not compensate for incomplete surgery [33]. While some working groups have been able to show that postoperative administration
of a hormonal contraceptive resulted in a reduction in the recurrence rate [135], [169], [182], two other prospective, randomized, placebo-controlled trials showed low recurrence
rates irrespective of the treatment arm [8], [170].
Patient information – Ovarian endometriosis
An endometriotic ovarian cyst should be removed completely by means of laparoscopy.
Hormonal treatment alone is not sufficient.
3.4 Deep infiltrating endometriosis
Core statements:
-
Deep infiltrating endometriosis (DIE) is defined as the involvement of the rectovaginal
septum, the vaginal fornix, the retroperitoneum (pelvic side wall, parametrium), the
bowel, ureter, and urinary bladder.
-
The primary diagnosis is made clinically with rectovaginal palpation, inspection with
divided specula, transvaginal ultrasound and transabdominal ultrasound of the kidneys
being mandatory.
Recommendations:
-
For treatment, complete resection should be performed. Nonetheless, compromises must
be made as preservation of fertility often is imperative. The extent of the resection
should be decided in close agreement with the patient against the background of benign
disease and possible relevant complications.
-
The treatment of DIE should take place in dedicated specialist centers on the basis
of an interdisciplinary approach.
-
In the case of conservatively managed patients and before and after surgery, kidney
ultrasound is mandatory in order to avoid overlooking clinically silent hydronephrosis.
Hydronephrosis associated with DIE is an absolute indication of appropriate diagnosis
and treatment.
3.4.1 Symptoms
DIE refers to the forms which manifest in the rectovaginal septum, in the vaginal
fornix, in the retroperitoneum (pelvic side walls, parametrium) and in the bowel,
ureter and urinary bladder. In the case of ureteral endometriosis, a distinction is
made between the intrinsic (infiltration of the ureter itself; rare) and extrinsic
(external compression) subtypes. The way in which the aforementioned structures are
involved may be very complex [189].
The symptoms depend on the site. In the case of bowel involvement, various intestinal
symptoms occur, including dyschezia, feeling of pressure, flatulence, tenesmus, blood
and mucus in the stool, diarrhea and constipation, and altered bowel habits. The absence
of symptoms does not rule out bowel involvement. Endometriosis of the bladder can
cause voiding difficulties and hematuria. Ureteral endometriosis can lead to hydronephrosis.
Endometriosis-induced back-up of urine develops slowly and is, therefore, usually
clinically silent [177]. Dyspareunia is typically caused by alteration of the pelvic plexus [154]. Although most patients with DIE complain of a variety of bowel symptoms, it has
not been possible so far to reproduce any sensitive anorectal dysfunction by means
of manometry in studies on this subject [118].
Rectovaginal septum involvement is most common, followed by involvement of the rectum,
the sigmoid colon, the cecum and the vermiform appendix, the bladder and ureters and,
much more rarely, the ileum while multiple sites involvement is possible.
3.4.2 Diagnosis
A clinical diagnosis of suspected disease is made initially on the basis of the patientʼs
history, which is often indicative, and on vaginal and rectal palpation, followed
by an investigation-based diagnosis by means of transvaginal ultrasound. Various investigations
have been found to be useful in connection with the subsequent work-up ([Tables 2] and [3]):
Table 2 Clinical investigations for the work-up of deep infiltrating endometriosis.
|
Investigation
|
Evidence provided
|
|
Inspection (double-bladed speculum)
|
Visible endometriosis in the posterior fornix
|
|
Palpation (always including rectal)
|
Uterus often retroverted; dense, nodular, tender infiltration of the rectovaginal
septum (retrocervical)
|
|
Transvaginal ultrasound
|
Changes in the uterus in the presence of concurrent adenomyosis and information about
possible ovarian endometriomas, good visualization of deep rectal involvement
|
|
Renal ultrasound
|
Be alert to back-up of urine (parametrial, pelvic wall and ureteral endometriosis)
|
Table 3 Optional investigations for the evaluation of deep infiltrating endometriosis.
|
Investigation
|
Evidence provided
|
|
Proctosigmoidoscopy
|
External impression, mucosal involvement (rare), differential diagnosis of primary
bowel disease
|
|
Magnetic resonance imaging
|
Involvement of the bowel wall, the bladder; adenomyosis?
|
|
Transrectal endoscopic ultrasound
|
Involvement of the bowel wall?
|
|
Contrast enema
|
Bowel involvement in higher sections
|
|
Intravenous pyelogram or computed tomography
|
Ureteral stenosis, hydronephrosis
|
|
Cystoscopy
|
Bladder involvement
|
Proctosigmoidoscopy is used very frequently in the presence of suspected rectosigmoid
involvement. However, infiltration of the mucosa is extremely rare. In the presence
of extensive disease, an external impression is rather to be expected – around 26 %
of patients with rectal endometriosis exhibit stenosis [161], so a negative proctoscopic mucosal finding is the rule, and by no means excludes
involvement of the muscularis. The importance of proctoscopy thus lies in the evaluation
of other causes of rectal bleeding as part of the differential diagnosis. MRI exhibits
a high sensitivity for the diagnosis of DIE and provides useful information [18]. Transrectal endoscopic ultrasound provides a reliable and simple means of predicting
the presence of deep rectal infiltration [18]. Transvaginal ultrasound also provides a straightforward means of DIE visualization,
including the diagnosis of deep rectal involvement with a high level of sensitivity
and specificity combined with minimal patient discomfort [87], [90]. In a comparative study, the aforementioned methods were found to be equivalent
overall in terms of diagnostic effectiveness, although MRI had the highest sensitivity
in some cases [18]; in another study, transvaginal ultrasonography was favored [3]. Regardless of the pre-operative diagnosis, the extent of the resection is often
not decided until during the operation (e.g. multiple intestinal foci: rectum, sigmoid
colon, cecum).
3.4.3 Treatment
The treatment of choice for symptomatic deep infiltrating endometriosis is resection,
leaving a free margin on all sides [42], [61], [98], [125], [127], [153]. In many studies, a positive effect on pain, overall quality of life and fertility
has been demonstrated [17]. Various methods are available for this: vaginal resection, laparoscopy, laparoscopically
assisted vaginal surgery, laparotomy. In the presence of infiltration-related manifestations
of endometriosis (rectosigmoid colon, bladder, ureter), the pre-operative counseling
for and planning and performance of the intervention should be carried out on the
basis of interdisciplinary consensus (including Visceral Surgery and/or Urology, depending
on the situation). If hydronephrosis is present (i.e., an absolute indication of treatment),
it is vital to refer the patient to a urologist who will carry out an assessment of
renal function and decide whether, how, and to what extent treatment should be carried
out [117]. If there is a desire to conceive, the need to preserve the uterus and ovaries often
results in incomplete resection of the endometriosis.
The benefits of the resection are to be confronted with the morbidity associated with
surgery [31], [36], [45], [154] as well as the recurrence rate of endometriosis. Recurrences after bowel resection
for DIE occur in about 14 % of cases (5–25 %, see [49], [124]). Complications, some of which can be severe (anastomotic leaks), must be anticipated
during surgery and in the immediate postoperative period in approx. 5–14 % of cases.
This applies especially to segmental rectal resection (associated with an incidence
of up to 24 %, see [108], [127], [147], [150], [160]), which is why some research teams warn against segmental rectal resection for benign
endometriotic disease and recommend the mucosa-sparing “shaving” technique or full-thickness
resection of the wall without in-continuity resection [54], [69]. The long-term consequences – some of which being irreversible – must always be
weighed against the desired positive effect of the operation. Besides fistula and
rectal dysfunction [13], bladder atony – sometimes associated with the need for permanent self-catheterization
by the patient – is of particular clinical relevance [15], [160]. This is caused by surgical alteration of the hypogastric plexus (splanchnic nerves)
which is unavoidable in some cases. The risk of postoperative bladder atony with self-catheterization
was stated as 29 % in one study; the risk was associated with simultaneous partial
colpectomy [210]. Whether nerve-sparing surgical techniques can prevent such urological complications
is under investigation [37], [97]. A particular situation also arises when complex colorectal and urological procedures
are performed in one session – in these cases, it is important to consider whether
it would not be better to adopt a two-step approach [159].
Owing to the complexity of the procedures, surgical treatment of DIE should be carried
out in centers with relevant experience [56]. Asymptomatic findings should always be monitored with the inclusion of renal ultrasound,
and do not necessarily require surgery in the absence of progression. Spontaneous
bowel perforation and ileus are extremely rare [51]. Because of the risk of these occurring, however (e.g., including during pregnancy
with considerable maternal and fetal consequences in some cases), the pros and cons
of a deliberate decision not to operate should also be discussed in detail. This gives
rise to the dilemma that both surgery for deep rectovaginal endometriosis and leaving
it in situ may possibly result in a higher risk of spontaneous perforation/vulnerability
during pregnancy and delivery (posterior vaginal fornix rupture), which is attributed
to decidualization during pregnancy [24], [41], [152]. Against this background, the primary method of delivery (spontaneous delivery versus
cesarean section) is a subject which should definitely be broached with the patient
and considered carefully (expert opinion, Weissensee meeting of the Endometriosis
Research Foundation, 2013). Conclusion: Possible surgical and non-surgical alternatives
for DIE must always be explained in both directions (documentation).
The benefit of pre- or postoperative GnRH analog therapy for deep infiltrating endometriosis
is not proven [33], [64], and, therefore, cannot generally be recommended. Medical hormonal therapy will
be given, however, if the patient wishes to avoid surgery or if there are postoperative
symptoms. An effect can only be expected during therapy, and long-term treatment is
therefore necessary. Progestin monotherapy, a monophasic continuous oral contraceptive
or GnRH analogs (with add-back therapy) for the induction of therapeutic amenorrhea
are options. Another possible alternative to surgery is the insertion of a levonorgestrel-releasing
IUD under which pain relief and a reduction in rectovaginal endometriosis size have
been observed [59].
Estrogen and progestogen replacement therapy in endometriosis
Premenopausal patients following hysterectomy for endometriosis receive combined estrogen
and progestin replacement therapy if indicated. In postmenopausal women, estrogen
and progestogen combinations or tibolone are also recommended following hysterectomy
in view of the fact that there is a risk of recurrence and malignancy (see section
entitled “Endometriosis-associated malignancies”) [129], [175]. The problem of the risk of breast cancer must nevertheless be weighed against this
and discussed with the patient so that an individual decision can be made (AWMF-S3
Guideline: Hormone replacement therapy in peri- and postmenopausal women, AWMF Registry
no. 015-062, 2009).
Patient information – Deep infiltrating endometriosis
Where endometriosis involves the vagina, bowel, bladder and ureters, complete surgical
removal of the lesions is the best treatment at present. Extensive surgery is often
needed for this, which requires good cooperation between gynecologists, surgeons and
urologists and should be performed in a dedicated specialist unit. Before surgery
for deep infiltrating endometriosis, the risks and benefits must always be weighed
up carefully, because even extensive surgery with complete removal of the endometriosis
cannot guarantee the desired pain relief which is the aim of surgery.
3.5 Uterine adenomyosis
Core statement:
The diagnosis of adenomyosis is primarily established clinically, by vaginal ultrasound
and/or MRI; confirmation is usually provided only by the histological findings based
on the hysterectomy specimen.
Recommendations:
-
Given completion of family planning and presence of respective symptoms, hysterectomy
can be recommended.
-
If the patients opts for preservation of the uterus, therapeutic amenorrhea may be
induced or a progestin-releasing IUD inserted.
3.5.1 Symptoms
Adenomyosis is defined as the infiltration of the myometrium by endometriosis. The
main symptoms are painful, heavy and acyclic bleeding together with infertility [65].
3.5.2 Diagnosis
In clinically suspected cases, the following investigations have proved effective
([Table 4]):
Table 4 Work-up for adenomyosis.
|
Measure/investigation
|
Finding
|
|
Past medical history
|
Dysmenorrhea (including with neurodystonia), hypermenorrhea
|
|
Clinical examination
|
Occasionally tender, enlarged uterus (bimanual, rectovaginal palpation)
|
|
Transvaginal ultrasound
|
Poorly demarcated heterogeneous areas, cystic intramural changes in some cases, areas
of variable echogenicity, irregular halo effect, discrepancy between anterior and
posterior wall
|
|
MRI
|
Changes in the zonal anatomy of the uterus, Irregular junctional zones on T1- and
T2-weighted images, areas of low signal intensity and subendometrial foci of high
signal intensity, anterior-posterior wall asymmetry as a sign of muscle hyperplasia
|
Transvaginal ultrasound is of greatest significance in day-to-day practice with approx.
65–70 % sensitivity and 95–98 % specificity [89], [123]. MRI, with high sensitivity and specificity for the diagnosis of adenomyosis, is
also suitable and useful in individual cases [38], [101], [104], [149].
Although desirable, there is no suitable routine method for the histologic confirmation
of adenomyosis. Various groups have worked on biopsy methods, while only positive
results are exploitable. It cannot be used to rule out the disease (e.g. [99]).
The definitive diagnosis, therefore, is ultimately based on the hysterectomy specimen
in most cases. Adenomyosis can occur in isolation or together with various forms of
endometriosis. DIE is often associated with adenomyosis [110].
3.5.3 Treatment
If the patientʼs family planning is complete, hysterectomy represents the most effective
treatment [65]. The decision regarding which method to be used for this (vaginal, abdominal, laparoscopically
assisted vaginal, total laparoscopic, laparoscopic supracervical) is left to the discretion
of patient and surgeon. Vaginal hysterectomy on its own without simultaneous laparoscopy
rules out the possibility of peritoneal implant removal, however, and should therefore
be the exception. Laparoscopic supracervical hysterectomy (LASH) appears to be suitable
for this indication with careful reference to the S1 Guideline of the German Society
for Obstetrics and Gynecology (AWMF no. 015-064) as the cervix is involved only in
extremely rare cases [14], [166]. Irrespective of this general recommendation of hysterectomy, consideration must
still be given to the potentially negative consequences of hysterectomy in women with
chronic pelvic pain (AWMF Guideline of the German Society for Psychosomatic Obstetrics
and Gynecology, AWMF no. 016-001).
The benefit of uterus-preserving surgical treatment for patients wishing to conceive
or desiring organ preservation in focal forms of adenomyosis is not demonstrated by
studies. If this is attempted in individual cases (e.g. encouraging results by [142]), an MRI scan or preoperative administration of a GnRH analog may be useful for
planning the operation [133], [143], [149]. The risk of uterine rupture during pregnancy or childbirth, especially if larger
myometrial defects arise, should be taken into account in the subsequent management
of the patient [149], [201].
The use of interventional radiology procedures for the treatment of adenomyosis, such
as embolization [26] and MRI-guided focused ultrasound ablation [63], hitherto, should be limited to studies.
Progestogins, oral contraceptives and progestin-releasing intrauterine systems are
used as an alternative to hysterectomy [58]. The therapeutic effect is based on the induction of amenorrhea. Contraceptives
(monophasic products) and progestins should be taken continuously [44], [195].
4 Endometriosis and Infertility
4 Endometriosis and Infertility
Core statements:
-
While a causal relationship has not been resolved yet, endometriosis and infertility
are frequently associated.
-
For the treatment of women with both endometriosis and infertility, appropriate skills
and experience in infertility surgery as well as cooperation with centers for reproductive
medicine are required.
Recommendations:
-
In women with endometriosis who wish to conceive, implants should be removed surgically
to improve fertility.
-
In cases of recurrence, assisted reproductive technologies are superior to repeat
surgical interventions in terms of the pregnancy rate. In repeat operations for ovarian
endometriosis, the surgery-related potential reduction in ovarian reserve is to be
considered.
-
Postoperative treatment with GnRH analogs has not been effective in improving the
spontaneous pregnancy rate in infertility patients and is, therefore, not recommended.
-
Any drug treatment of endometriosis alone does not improve fertility and should not
be applied from a reproductive medicine perspective.
4.1 Pathophysiology of infertility associated with endometriosis
Infertility and endometriosis are often associated, although it is not clear whether
there is a causal relationship. Mechanical alteration of the adnexa is unequivocally
accepted as the cause of infertility. However, whether the endometriosis creates an
immunologically “hostile” environment for implantation or whether it leads to impairment
of sperm transport, Fallopian tube mobility and oocyte maturation is unclear [102]. Nevertheless, results from egg donation programs indicate that oocyte and early
embryonic development may be impaired in women with endometriosis [66].
4.2 Medical and surgical treatment
Medical treatment alone
In the presence of rASRM stage I and II endometriosis, no improvement in fertility
was shown in a meta-analysis of 16 randomized and controlled studies following medical
treatment (GnRH analogs, progestins) compared with placebo or a wait-and-see approach
[92].
Surgical treatment
a) Minimal and mild endometriosis (in accordance with rASRM)
Two randomized, controlled studies on the effect of surgical removal (coagulation/excision)
of endometriotic lesions in patients with infertility and AFS stage I and II endometriosis
have been identified: Marcoux et al. [119] and Parazzini et al. [146]. Marcoux et al. randomized a total of 341 patients (average age: 30.5 years, average
duration of infertility: 31 months) intraoperatively. Over a follow-up period of 36
weeks, 30.7 % of the patients in the group who underwent excision of the endometriosis
(50 out of 179) became pregnant compared with 17.7 % (29 out of 169; cumulative incidence
ratio 1.7; 95 % CI 1.2–2.6) in the group who underwent diagnostic laparoscopy alone.
The birth rate was not given. Parazzini et al. [146] intraoperatively randomized 101 patients with ASF stage I and II endometriosis who
had experienced infertility for 38 months on average. During the follow-up period
of at least one year, 12 patients in the excision group (12 out of 54 = 22.2 %) and
13 in the diagnostic laparoscopy group (13 out of 47 = 27.6 %) became pregnant. No
statistically significant difference was found between the results, including in terms
of birth rate of n = 10 in each group. In a meta-analysis based on these two studies,
Jacobson et al. [94] came up with a positive overall result with respect to a benefit of excision in
terms of an improved pregnancy rate, although the magnitude of the effect was uncertain
(odds ratio 1.66; 95 % CI 1.09–2.51). The confidence interval shows the possible variability
in the actual effect in the presence of non-parallel results for the two studies.
In a retrospective cohort study (n = 661) of patients with AFS stage I and II endometriosis
undergoing IVF, a 10.7 % increase in the first IVF cycle pregnancy rate (29.4 % compared
with 40.1 %, p = 0.004) and a 6.9 % increase in the birth rate (p = 0.04; [140]) was found in those patients (n = 399) whose endometriotic lesions were excised
before IVF.
b) Deep infiltrating endometriosis
No controlled, randomized studies are available for deep infiltrating endometriosis
including bowel involvement in which the primary objective was to compare surgical
against non-surgical treatment in terms of the pregnancy and birth rates. Some non-randomized
studies show that excision of DIE may improve the spontaneous and IVF-induced pregnancy
rate [23], [39], [46], [69], [98], [115], [179].
In deep infiltrating endometriosis with bowel involvement, a prospective cohort study
showed a significantly higher IVF-induced pregnancy rate when complete surgical removal
was performed before [23]. Another prospective cohort study showed a higher pregnancy rate in patients with
bowel endometriosis who underwent segmental rectosigmoid resection compared to leaving
the bowel endometriosis in place (28.3 % compared with 20 % p-value not specified;
[179]). In another study in pregnant women with DIE who wished to conceive, spontaneous
pregnancies were observed only after laparoscopy compared with open surgery [46]. The outcome of a case-control study, on the other hand, indicated that radical,
retroperitoneal excision of DIE did not confer any additional benefit in terms of
reproductive function (and was associated with a significantly higher complication
rate) compared with removal of intraperitoneal lesions alone [55].
In patients with endometriotic cysts, endometrioma excision is superior to fenestration
and coagulation in terms of the spontaneous pregnancy rate [7], [76]. Preoperative medical treatment does not improve the outcome [53], [76].
Postsurgical medical treatment
Postsurgical treatment with GnRH analogs did not produce an improvement in the spontaneous
pregnancy rate in infertility patients and is, therefore, not recommended [33], [92].
4.3 Assisted reproduction
Intrauterine insemination (IUI)
In the presence of minimal and mild endometriosis, IUI leads to an improvement in
the pregnancy rate, while some studies have shown a benefit of ovulation induction
compared with spontaneous cycles prior to IUI in terms of the pregnancy [48] and live-birth rate [185]. In one study, in contrast to the initial hypothesis, the cumulative endometriosis
recurrence rate after 21 months was significantly higher following stimulation for
IUI cycles than following controlled ovarian hyperstimulation for IVF [52].
In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI)
Data from national treatment registries and current retrospective analyses show similar
pregnancy rates following IVF in endometriosis patients compared with patients with
tubal factor infertility [141]. Thus, conflicting results in a previous review could not be confirmed [16].
The effect of ovarian endometriomas on the outcome of IVF is unclear. Systematic reviews
have shown that surgical treatment for endometriomas is not a prerequisite for success
of IVF (i.e. with regard to pregnancy rates) [22], [184]. On the other hand, it makes needle insertion easier and reduces the risk of infection.
Consideration must also be given to the (very rare) possibility of ovarian cancer
arising from endometriosis [120], [130]. The question of whether doing without surgery in patients who are desperate to
conceive in view of the ovarian reserve potentially being compromised by the ablation
[43] arises in the presence of bilateral and recurrent endometriomas in particular [34], [176]. The individual decision, based on these considerations, not to operate or re-operate
(and thus to do without a histologic analysis or complete excision of the endometriosis
as is desirable) but with the risk of relevant ovarian disease being overlooked, is
a difficult one and should be made only in consultation with the patient, taking into
account existing symptoms, safety concerns and differential diagnostic considerations
[34]. If loss of ovarian function is imminent, some authors have considered cryopreservation
of oocytes following ovarian stimulation or of ovarian tissue as an option for very
young women not wishing to conceive at the present time [57].
In cases of recurrence of extensive endometriosis, assisted reproduction is superior
to repeat surgical treatment in terms of the pregnancy rate [145]. Considerations regarding whether to operate yet again or to attempt assisted reproductive
techniques without intervention should take into account the tubal status, duration
of infertility, the patientʼs age, the extent of the endometriosis and the endometriosis-induced
symptoms not associated with infertility, along with the patientʼs wishes [6]. Although the possibility of endometriosis exacerbation during stimulation for IVF
should be considered this has not been demonstrated in controlled studies [20], [21]; nevertheless, the cumulative rate of endometriosis recurrence was 7 % for IVF cycles
after 21 months in one study [52]. As a general rule, the more extensive the endometriosis and the older the patient,
the earlier assisted reproduction should be recommended [107]. Nevertheless, younger patients with endometriosis who wish to conceive should also
definitely be made aware of this option. According to a systematic Cochrane review,
ultra-long GnRH analog therapy after surgical treatment and (3–6 months) prior to
IVF/ICSI leads to significantly higher pregnancy rates in rASRM stage III and IV endometriosis
[158], [163].
Patient information – Infertility and endometriosis
The surgical removal of endometriotic lesions is generally recommended in women who
wish to conceive. It has been shown that an improvement in fertility can be achieved
with surgery alone if the Fallopian tubes were intact and the sperm analysis normal.
The treatment of these patients should be left in expert hands. If endometriosis recurs
(particularly after several operations), in vitro fertilization is a better way to
achieve pregnancy than undergoing surgery again.
5 Psychosomatic Aspects
Recommendation:
Psychosomatic aspects in the treatment of patients with endometriosis should be considered
and integrated early on.
Even if the evidence suggests that the pain a woman is suffering is caused by the
presence of endometriosis, this does not rule out emotional conflict or psychosocial
stress as co-factors. Generally speaking, chronic pelvic pain is accompanied by a
considerable loss of quality of life and is frequently associated with a somatoform
pain disorder (Guideline: Chronic pelvic pain in women, AWMF Registry no. 016-001).
A desire to conceive and dysfunctional sick-role behavior (e.g. avoidance of physical
activity), which can have an exacerbating effect on pain, leading to a vicious circle,
may be additional psychological stress factors in endometriosis.
The integration of psychosomatic approaches to treatment for patients with chronic
pelvic pain against a background of endometriosis (as an adjunct to surgical and medical
measures) may, on the other hand, improve the patientsʼ quality of life and their
handling of the chronic pelvic pain and thus have a positive influence on treatment
outcomes [50], [173]. The integration of sex counseling into psychological support is also important.
Many authors are now calling for multidisciplinary approaches to treatment when it
comes to dealing with chronic pelvic pain [35], [116], [178], [203]. Causes other than endometriosis should also always be considered in the differential
diagnosis of chronic pelvic pain [173], [174].
In addition, there are some epidemiological studies that suggest an association between
endometriosis and other chronic pain conditions such as migraine and chronic irritable
bowel syndrome [111], [183].
6 Complementary and Integrative Approaches to Treatment
6 Complementary and Integrative Approaches to Treatment
Core statement:
Owing to the lack of controlled, randomized studies to date on complementary and integrative
approaches to the treatment of endometriosis, no recommendations can be made.
Women with chronic recurrent endometriosis and corresponding symptoms may obtain relief
of symptoms and an improvement in quality of life from the use of complementary therapies
[208]. In particular, these include the methods of acupuncture and Chinese medicine, classical
homeopathy, herbal medicine, physiotherapy, etc. This should always be preceded by
appropriate clinical screening for potential organ changes (endometriomas, hydronephrosis).
Although results from larger scale, randomized and controlled studies are not yet
available, initial investigations clearly point to acupuncture [209] and Chinese herbal medicine having an effect on endometriosis-induced pain [60].
7 Rehabilitation, Follow-up and Self-help
7 Rehabilitation, Follow-up and Self-help
Core statement:
After extensive surgical interventions (particularly for deep infiltrating endometriosis),
repeat surgery for endometriosis, or in patients with chronic pain, there is often
a need for rehabilitation.
Recommendation:
This need should be assessed and rehabilitation measures or follow-up treatment initiated.
All efforts in the area of rehabilitation are focused on the restoration of physical,
mental and social well-being. Coping with a disease that frequently follows a chronic
course and is sometimes associated with unavoidable limitations and pain is also an
important aspect, however. In Germany, specialist centers exist that have considerable
experience in the rehabilitation of endometriosis patients.
Follow-up should be based on symptoms, with the focus being on the patientʼs quality
of life. All doctors should be aware of the limitations of the treatment options –
particularly in cases where the endometriosis keeps recurring.
Self-help options exist to assist women with endometriosis in coping with the physical
and mental problems they face. The independent endometriosis associations in Germany
and Austria, the members of which are sufferers themselves, represent the interests
of women with endometriosis. Besides free advice, they can provide addresses of self-help
groups, rehabilitation centers and specialist doctors.
Patient information – Rehabilitation and aftercare
Following extensive surgery for endometriosis, additional follow-on treatment is also
helpful. The medical treatment of endometriosis has its limitations. Even after careful
surgery in the hands of an expert, many patients continue to suffer from chronic pain
– even if all the endometriosis was removed successfully. And not all women wishing
to conceive will manage to become pregnant. In order to cope with the physical and
mental problems that women with endometriosis can face, patients should be informed
about the opportunities for self-help. The independent endometriosis associations
in Germany and Austria, the members of which are sufferers themselves, represent the
interests of women with endometriosis. Besides free advice, they can provide addresses
of self-help groups, rehabilitation centers and specialist doctors in the different
regions.
8 Summary
Endometriosis is one of the most common gynecological diseases. Women affected may
suffer a considerable loss of quality of life [96]. Besides the individual health problem, the economic impact caused by the high level
of morbidity, reduced work productivity and repeated therapeutic interventions should
also be considered.
The etiology and pathogenesis are unclear. There is no known causal therapy. Laparoscopic
removal is considered to be the surgical “gold standard”. Because the patients affected
often wish to conceive and organ preservation is a top priority, radical surgery must
often be limited. A patient with asymptomatic endometriosis who does not wish to conceive
does not generally need to be treated (exception: hydronephrosis).
Careful patient selection and good interdisciplinary cooperation are prerequisites
for surgical therapy in cases of endometriotic infiltration of the bowel, urinary
bladder and/or ureter. The extent of surgery must always be weighed up against the
morbidity associated with surgery and the unavoidable tendency to recur.
Counseling regarding alternatives to surgery (medical treatment) must be documented
as carefully as any decision by the patient not to undergo surgery (despite a clear
indication).
While pre-operative medical treatment is not recommended with the products available
at present, postoperative administration may prolong the recurrence-free interval
in cases of peritoneal endometriosis. Various medical options for the treatment of
pain symptoms can be considered as an alternative to the surgical approach or in the
event of problems with recurrence, with progestins, monophasic oral contraceptives
and GnRH analogs (with concomitant add-back medication to eliminate hypo-estrogenic
side effects) having similar efficacy with different adverse effect profiles. Progestin-releasing
intrauterine systems are another option.
Hormone therapy alone does not result in an improvement in fertility in endometriosis.
Surgical removal of the endometriosis and the associated sequelae increased the spontaneous
pregnancy rate in some studies. In the presence of severe endometriosis with destruction
of organs (i.e. tubes and ovaries), assisted reproduction may be a better option,
although surgery beforehand may increase the associated pregnancy rate. There are
other reasons (pain, disease unrelated to pregnancy) for which such surgical correction
should be considered in individual cases before planned assisted reproduction.
Almost all patients with endometriosis require medication for pain relief in the course
of their disease. Depending on the circumstances, professional pain therapy should
be provided, with psychosomatic support where necessary.
9 Important Internet Addresses
The validity of the guideline has been approved by the Board of the DGGG [German Society
for Gynecology and Obstetrics] and the DGGG Guidelines Commission in August 2013.
The guideline will remain valid until September, 2016.
Oral contraceptives and levonorgestrel-releasing intrauterine systems are not approved
for the treatment of endometriosis in Germany. They can, therefore, only be used on
an off-label basis.
