Treatment of endometriosis-associated pain
Medical treatment
Non-steroidal anti-inflammatory drugs
First-line medical treatment of pain due to endometriosis is often a non-steroidal anti-inflammatory drug (NSAID). Good evidence exists to support the use of NSAIDs for primary dysmenorrhea (62), but in a Cochrane meta-analysis there were insufficient data to show that NSAIDs significantly reduce endometriosis-associated pain (63).
It has to be noted that only two studies were available that investigated the role of NSAIDs in the relief of endometriosis-associated pain (63). Nevertheless the ESHRE 2014 guideline recommends that clinicians should consider NSAIDs or other analgesics to reduce endometriosis-associated pain, due to the known benefit of NSAIDs in primary dysmenorrhea (2).Oestrogens and progestogens
The clinical observation of apparent symptom resolution during pregnancy gave rise to the concept of treating patients with a pseudopregnancy regimen (64). In 1958, Kistner was the first to use combinations of high-dose oestrogens and progestogens, and later progestogens alone (64). Decidualization followed by atrophy of both the eutopic and ectopic endometrial tissue is the generic proposed mechanism of action (38). Additionally, COCs might have a positive effect on endometriosis through reduction of the menstrual blood flow, downregulation of cell proliferation, and enhancement of programmed cell death in the eutopic endometrium (65). Similar to COCs, the chronic administration of progestogens results in decidualization and subsequent atrophy of endometrial tissue (38). Recent research also suggests a possible role of progestogen-induced suppression of matrix metalloproteinases, a class of enzymes important in the growth and implantation of ectopic endometrium, and inhibition of angiogenesis (38).
A Cochrane systematic review from 2007 addressed the use of COCs for pain associated with endometriosis (64).
Surprisingly only one study was found, despite the widespread use of COCs in clinical practice (66). In the included study, no significant difference between treatment with a COC and a GnRH agonist was seen (66). Based on this study and on the widespread use of COCs, both the 2013 ESHRE and the ASRM 2014 guideline recommend the consideration of a COC, vaginal contraceptive ring, or transdermal patch in the treatment of endometriosis-associated pain.The body of evidence supporting the use of progestogens and antiprogestogens in the treatment of endometriosis-associated pain is larger than for COCs. In their systematic review from 2012, Brown and colleagues included 13 articles evaluating progestogens and antiprogestogens (67). Of the two studies comparing progesto- gens with placebo, only one showed a significant effect. There was no overall evidence of a benefit of progestogens over other medical treatments (COCs, GnRH agonists). The authors concluded that the evidence for progestogens in the treatment of endometriosis pain was limited (67). The 2014 ESHRE guideline considers this evidence as sufficient to recommend the use of some specific progestogens (medroxyprogesterone acetate, dienogest, cyproterone acetate, norethisterone acetate, levonorgestrel-releasing intrauterine system, or danazol) and antiprogestogens (gestrinone) (2). Due to its severe side effects (acne, oedema, vaginal spotting, weight gain, and muscle cramps) the use of danazol is discouraged, and should only be considered if no other medical therapy is available (2).
GnRH agonists
GnRH agonists are synthetic analogues of GnRH that differ from the native hormone with respect to the specific amino acid sequence (68). All are designed either to increase receptor affinity or decrease GnRH degradation (68). Their use therefore leads to persistent activation of GnRH receptors (68). This activation results in an initial release of gonadotropins previously produced and stored in the pituitary (68).
However, the release is rapidly followed by downregulation of GnRH receptor expression and profound suppression of gonadotropin secretion (68). As a result, sex-steroid production in the ovary falls to levels similar to those seen after castration (68). This profound hypo-oestrogenic state inhibits the development, maintenance, and growth of endometriosis, which in turn alters the effect on the immune, nervous, and endocrine systems. The hypo-oestrogenaemia also has direct effects on these systems, further altering their status from that seen in patients with active endometriosis (68). The hypo- oestrogenism induced by GnRH agonists can result in bone loss and severe hypo-oestrogenic symptoms (disturbed sleep pattern, hot flushes, vaginal dryness, etc.). To reduce the negative effects of oestrogen deprivation, hormonal add-back therapy with oestrogens and/or progestogens or tibolone is recommended (2). This is based on the threshold theory, by which lower oestrogen levels are needed to protect the bone and cognitive function and to avoid/minimize menopausal symptoms than to activate endometriotic tissue (69).GnRH agonists have been studied more extensively for the treatment of endometriosis-associated pain than other medical therapies (68). Multiple randomized trials have pitted GnRH agonists against other known treatments for endometriosis, including COCs, pro- gestogens, and danazol. A Cochrane review compared GnRH agonists at different doses, regimens, and routes of administration, with danazol, intrauterine progestogens, placebo, and analgesics for relieving endometriosis-associated pain symptoms (70). The metaanalysis showed that GnRH agonists were superior to no treatment or placebo for dysmenorrhea and pelvic tenderness with a significant improvement of the Endometriosis Severity Symptom Score. There were no statistically significant differences when GnRH agonists were compared with the levonorgestrel-releasing intrauterine system or oral danazol for dysmenorrhea, dyspareunia, pelvic pain, and pelvic tenderness.
Intrauterine progestogens and oral danazol showed a better side effect profile than GnRH agonists without add- back therapy (70). Several studies have demonstrated that add-back therapy reduces the side effects of GnRH agonist treatment without a negative effect on the efficacy of treatment with GnRH agonists (71-74). It can be concluded that GnRH agonists are effective in the relief of endometriosis-associated pain, but evidence is limited regarding dosage or duration of treatment. The severe side effects of monotherapy should be taken into account and therefore the ESHRE guideline recommends that hormonal add-back therapy should be associated from the start of the treatment with GnRH agonists (2). Future studies should compare novel therapies with GnRH agonist with add-back therapy to allow clinically meaningful comparisons.Aromatase inhibitors
Aromatase inhibitors (AIs) constitute another class of drugs that cause hypo-oestrogenism and are used in the treatment of endometriosis. AIs suppress oestradiol production through reversible (an- astrozole, letrozole) or irreversible (exemestane) inhibition of the aromatase P450 enzyme resulting in hypo-oestrogenism (75). The aromatase P450 enzyme plays an important role in the production of oestradiol by converting androstenedione to oestrone (E1) (76). Subsequently, E1 is converted to oestradiol (E2) by the activity of 17- OH-steroid dehydrogenase (76). E2 is mainly produced by the ovary in a cyclic fashion, where it is secreted by the preovulatory follicle. In addition, there is conversion of circulating androstenedione of adrenal origin to E1 in peripheral tissues such as fat, skin, and skeletal muscle (76). There is some evidence that endometriotic tissue, unlike disease-free endometrium, might exhibit a high level of aromatase activity that may result in increased local concentrations of oestradiol that may favour the growth of endometriosis (77). Even though the evidence for increased expression of aromatase P450 in endometriotic tissue is limited and still controversial, AIs have been studied as treatment for pain symptoms in premenopausal women with endometriosis.
A systematic review evaluating the use of AIs to treat endometriosis associated-pain concluded that the existing evidence is of moderate quality and that evidence on the long-term effects are lacking (78). Like GnRH agonists without add-back, AIs have severe side effects such as vaginal dryness, hot flushes, and diminished bone density. Furthermore, in premenopausal women AIs lead to an increase in follicle-stimulating hormone levels and subsequent follicular development and therefore must be used in combination with other agents (progestogens, COCs, or GnRH agonists) to downregulate the ovaries (38). Treatment of endometriosis-associated pain with AIs should be considered experimental and only be prescribed to women after all other options for medical or surgical treatment are exhausted (2, 38).
Surgical treatment
The goal of endometriosis surgery must be to remove all lesions and associated adhesions in order to restore normal anatomy, with attention to preserving fertility. Surgical options for the treatment of endometriosis include surgical excision or ablation and may be performed robotically, laparoscopically, or through laparotomy. Although laparoscopy and laparotomy are equally effective, the laparoscopic approach is now considered routine for the diagnosis and removal of endometriosis as it results in less pain, decreased recovery time, and better cosmetic results (79).
Peritoneal endometriosis
Several randomized controlled trials have evaluated the efficacy of laparoscopic treatment in reducing endometriosis-associated pain compared with diagnostic laparoscopy alone (80). Meta-analysis of these data in a Cochrane review showed that surgical treatment by excision, coagulation, or laser vaporization of endometriotic lesions reduces overall pain associated with endometriosis and is more effective in pain reduction than diagnostic laparoscopy alone (80).
When considering the different types of pain, including pelvic pain, dysmenorrhea, dyspareunia, and dyschezia, there is insufficient evidence to determine which pain type responds best to laparoscopic surgery (80).
Two randomized controlled trials compared excision and ablation of endometriosis and found no difference in pain scores up to 1 year after surgery (81, 82). However, the conclusions of these studies should be treated with caution because of the small population of the trial by Wright and colleagues and the sub- optimal design of the trial by Healy and colleagues. Consequently, both ASRM and ESHRE recommend surgical treatment of endometriosis when it is identified at laparoscopy since it is effective for reducing endometriosis-associated pain (2, 38). Neither of the guidelines favours excision or ablation, but the ESHRE guidelines states that excision of lesions could be preferred with regard to the possibility of retrieving samples for histology (2, 38).Endometriomas
Medical therapy for ovarian endometriomas may lead to a temporary reduction in size of the cysts but not complete resolution (38). Surgery is therefore the primary approach for symptomatic or large endometriomas (38). Two surgical approaches can be used for endometriomas: draining and coagulation or cystectomy. A simple draining and coagulation involves opening, aspiration, and irrigation of the cyst followed by destruction/ablation/coagulation of the mucosal lining of the cyst. During cystectomy, the endometrioma is opened and aspirated followed by removal of the cyst wall from the ovarian cortex, with maximal preservation of normal ovarian tissue.
A cystectomy is superior to a simple draining and coagulation, due to a reduction in endometriosis-associated pain and to a carbon dioxide laser evaporation because of a reduction in recurrence of the endometrioma (83, 84). However, with cystectomy there is concern about the risk of ovarian damage and impaired ovarian reserve. A meta-analysis of eight studies on ovarian cystectomy for endometriomas found significantly lower anti-Mullerian hormone levels postoperatively (85). Bilateral cystectomy of ovarian endometriomas is associated with a 2.4% risk of ovarian failure (86). Therefore it is recommended that clinicians counsel women with an endometrioma regarding the risks of reduced ovarian function and ovarian failure after surgical treatment of endometriomas (2).
Deep endometriosis
Deep endometriosis is characterized by involvement of different pelvic and extrapelvic organs with a very diverse and often severe anatomical distortion making surgical excision of deep endometriosis difficult and challenging (43). Similar to surgery for superficial endometriosis and endometriomas the final goal of surgical treatment of deep endometriosis is to achieve complete resection of all deep endometriosis lesions (87). To prevent multiple surgeries, complete excision should be performed in a one-step surgical procedure (87). Taking into account the multifocality of deep endometriosis, this often requires several associated surgical interventions. An overview of the most commonly used surgical interventions for deep endometriosis is presented in Table 45.2.
A large number of studies on surgical excision of deep endometriosis have been published but mainly in retrospective designs. A systematic review by Meuleman et al. found that pain and quality of life improvement was reported in most studies (88). In another review on bowel resection for colorectal endometriosis, the authors found excellent pain relief in most studies (89). Hence, surgical treatment is considered to be the treatment of choice for symptomatic deep endometriosis, but is complex and associated with significant complication rates (43). The ESHRE guideline on the management of women with endometriosis recommends that treatment of deep endometriosis should be performed by multidisciplinary teams in centres with specific expertise in this area (2).
Table 45.2 Overview of most commonly used surgical interventions for deep endometriosis
| Bowel endometriosis | |
| Bowel shaving | Superficial excision of bowel serosal and subserosal endometriosis (mechanically, with diathermy, laser, or other energy source) that does not require suturing/closure |
| Bowel partial thickness discoid excision | Selective excision of the bowel endometriosis lesion (mechanically, with diathermy, laser, or other energy source) without entering the bowel lumen, that requires suturing/closure (i.e. closure of a muscularis defect without a mucosal defect in the bowel wall) |
| Bowel full thickness discoid excision | Selective excision of the bowel endometriosis lesion (mechanically, with diathermy, laser, or other energy source) with opening of the bowel lumen followed by closure of the bowel Subtypes: Open full thickness disc excision: excision with opening of lumen followed by closure Closed full-thickness disc excision: excision with stapler |
| Bowel resection and re-anastomosis | Resection of a bowel segment affected by endometriosis followed by re-anastomosis by any means |
| Ureteral endometriosis | |
| Ureterolysis | Restoration of the normal mobility and anatomical position of the ureter through resection of adhesions and selective dissection of the ureter from a lesion, either mechanically or with diathermy, laser, or any other energy source Subtypes: Without opening of the ureteric wall With opening and re-suturing of the ureteric wall. |
| Ureteral segmental resection | Resection of a ureteral segment affected by endometriosis followed by ipsilateral uretero-ureteral re-anastomosis or ureteral reimplantation into the bladder |
| Bladder endometriosis | |
| Bladder shaving | Superficial excision of bladder serosal and subserosal endometriosis (mechanically, with diathermy, laser, or other energy source) that does not require suturing/closure |
| Bladder partial thickness excision | Selective excision of the bladder endometriosis lesion (mechanically, with diathermy, laser, or other energy source) without opening of the bladder mucosa that requires suturing/closure. (i.e. closure of a muscularis defect without a mucosal defect) |
| Bladder full thickness excision | Resection of an endometriosis nodule by full thickness partial resection of the bladder wall, including the mucosa and closure of the defect by suture or other device |
Source data from Vanhie, A., et al., Consensus on Recording Deep Endometriosis Surgery: the CORDES statement. Hum Reprod 2016;31(6):1219-23.
Several techniques for the excision of deep endometriosis lesions have been described and evaluated, but large, well-designed, prospective randomized controlled trials comparing different techniques are lacking (43). Therefore, the appropriate surgical approach for deep endometriosis remains controversial as little is known about the impact of the different types of surgery on complications, pain, the patients' quality of life, and reintervention and recurrence rates (87). The recently published Consensus On Recording Deep Endometriosis Surgery (CORDES) statement provides a Deep Endometriosis Surgical Sheet (DESS) to record in detail the surgical procedures for deep endometriosis and an international consensus on pre-, intra- and postoperative data that should be recorded in surgical trials on deep endometriosis (43). Future studies on surgical treatment of deep endometriosis should take into account the impact of extensive deep endometriosis surgery on quality of life, sexuality, and bowel and bladder function.
Hysterectomy and interruption of pelvic nerve pathways
Hysterectomy will not necessarily reduce or cure the symptoms of endometriosis. Furthermore, hysterectomy without bilateral salpingo-oophorectomy (BSO) was reported to have a sixfold risk for development of chronic pain recurrence and even an eightfold risk of repeated surgery (90). Therefore, hysterectomy with BSO should be reserved for women with debilitating symptoms who have completed childbearing and in whom other therapies have failed (38). Women should be informed of the limitations of a hysterectomy in the surgical treatment of endometriosis (2).
Laparoscopic uterosacral nerve ablation (LUNA) is a technique designed to disrupt the efferent nerve fibres in the uterosacral ligaments to decrease uterine pain for women with intractable dysmenorrhea (38). Presacral neurectomy (PSN) involves interrupting the sympathetic innervation to the uterus at the level of the superior hypogastric plexus (38). A Cochrane review analysed the effectiveness of surgical interruption of pelvic nerve pathways (91). No benefit of LUNA was found as an adjunct to conservative surgery for endometriosis. Therefore clinicians should not perform LUNA as an additional procedure to conservative surgery to reduce endometriosis-associated pain (2). PSN in addition to conservative surgery did result in a reduction of pain symptoms, but may be specific to midline pain and was associated with an increased risk of complications (bleeding, constipation, urinary urgency, etc.) (91).