**4. Treatment of pelvic pain and recurrent symptomatic endometriosis**

Several physiopathological mechanisms might explain the relation between endometriosis and pelvic pain: (i) recurrent cyclic micro-bleeding in the endometriotic lesions responsible for hyperpressure; (ii) production of inflammatory mediators by endometriotic lesions, which can stimulate the nerves; (iii) adhesions responsible for fixed position of pelvic structures; (iv) compression and/or infiltration of the sub-peritoneal nerve fibres by deep implants (Fauconnier & Chapron, 2005).

Women with pelvic pain and suspected endometriosis may be managed with empiric medical therapy prior to establishing a definitive diagnosis by laparoscopy. It is suggested analgesics and/or combined oral estrogen-progestin contraceptives for women with no more than mild pelvic pain and a GnRH agonist for those with moderate to severe pelvic pain. Although 80 to 90% of patients will have some improvement in symptoms with medical therapy, medical interventions neither enhance fertility nor diminish

Hormonal suppression has been used prior to surgery to decrease the size of endometriotic implants (Yap *et al*., 2004). However, there is no evidence that preoperative hormonal intervention decreases the extent of surgical dissection and recurrence rates, prolongs the

The hypothetical advantages of short-term postoperative medical treatment, including resorption of residual visible foci and sterilisation of microscopic implants, should result in a reduction of postoperative lesions and symptoms recurrence rates (Vercellini *et al.*, 2003). Progestins, danazol, estrogen-progestin pills, and GnRH agonists have been used in conjunction with laparotomy or laparoscopic conservative or definitive surgical treatment. Several trials have reported that these agents increase the duration of pain relief and delayed recurrence of symptoms (Kennedy *et al.*, 2005). However, a meta-analysis of eight trials, considered that postoperative hormonal suppression of endometriosis decreased recurrence rates, but there was no significant benefit for the outcomes of pain or pregnancy rates (Yap *et al.*, 2004). The main problem in interpreting the above data is the short-instead of long-term use of medications. In fact, the rationale for suggesting adjuvant therapy for a few months is far from clear. When this treatment is deemed opportune, oestrogenprogestogen combinations should be considered because of their tolerable side effects, limited costs, and antalgic efficacy similar to GnRH agonists and danazol (Kennedy *et al.*,

The lowest effective dose of hormone replacement should be used shortly after definitive surgery or as soon as menopausal symptoms arise. Avoidance of oestrogen-only treatment and the use of combined preparations or tibolone are suggested (Vercellini *et al.*, 2009). Oestrogen-only therapy has been associated with an increased risk of malignant

Several physiopathological mechanisms might explain the relation between endometriosis and pelvic pain: (i) recurrent cyclic micro-bleeding in the endometriotic lesions responsible for hyperpressure; (ii) production of inflammatory mediators by endometriotic lesions, which can stimulate the nerves; (iii) adhesions responsible for fixed position of pelvic structures; (iv) compression and/or infiltration of the sub-peritoneal nerve fibres by deep

Women with pelvic pain and suspected endometriosis may be managed with empiric medical therapy prior to establishing a definitive diagnosis by laparoscopy. It is suggested analgesics and/or combined oral estrogen-progestin contraceptives for women with no more than mild pelvic pain and a GnRH agonist for those with moderate to severe pelvic pain. Although 80 to 90% of patients will have some improvement in symptoms with medical therapy, medical interventions neither enhance fertility nor diminish

**4. Treatment of pelvic pain and recurrent symptomatic endometriosis** 

**3. Pre and postoperative medical therapy** 

duration of pain relief, or increases future pregnancy rates.

transformation of ectopic foci (Modesitt *et al.*, 2002).

implants (Fauconnier & Chapron, 2005).

**3.1 Preoperative medical therapy** 

**3.2 Postoperative medical therapy** 

2005).

endometriomas or adhesions, and they are more appropriately managed surgically (Kennedy *et al.*, 2005). The growing popularity and widespread diffusion of operative laparoscopy has fostered a spread of surgical procedures in women with endometriosis (Vercellini *et al.*, 2009). However, due to the relapsing tendency of the disease, postoperative recurrences are very common (20-40%), and a further surgical procedure is performed in 15- 20% of cases (Busacca *et al.*, 1998; Fedele *et al.*, 2006).

#### **4.1 Repetitive conservative surgery**

Conservative surgery preserves the uterus and as much ovarian tissue as possible. Very limited information is available on the effect of repetitive conservative surgery for recurrent symptomatic endometriosis in terms of postoperative pain relief (Vercellini *et al.*, 2009). Pain relief is achieved in most patients who undergo laparoscopic ablation of endometriosis and adhesiolisis. However, the long-term outcome appears suboptimal, with a cumulative probability of pain recurrence between 20% and 40% and a further surgical procedure between 15% and 20% (Fedele *et al.*, 2006; Vercellini *et al.*, 2009).

Busacca *et al.* (1998) compared surgical outcomes in patients reoperated either at laparatomy or at laparoscopy. The crude recurrence rates of moderate to severe dysmenorrhea, deep dyspareunia, and pelvic pain were, respectively, 22%, 30%, and 35% in the laparotomy group and 29%, 25%, and 32% in the laparoscopy group. The 24-month cumulative probability of recurrence of dysmenorrhea (34% and 43%, respectively) and non-cyclical pelvic pain was not significantly different in the two groups. However, in the patients operated by laparotomy, the rate of recurrence of deep dyspareunia and the number of patients requiring a third intervention was higher.

The effect of repetitive laparoscopic surgery on pain is similar to that observed after firstline surgery, with a 5-year cumulative pain recurrence rate of 20% after the first surgical procedure and 17% after the second one and cumulative rates of retreatment of 19% and 17%, respectively. This fact confirm the effectiveness of repeat conservative surgery in the treatment of recurrent pain, which is more likely to be associated with severe disease, adhesions and deep intraovarian or multilocular cysts (Fedele *et al.*, 2006).

High recurrence rate is the demonstration that surgery alone is a suboptimal treatment for a chronic disease such endometriosis. In order to possibly reduce recurrences of endometriosis, it is important that all surgical procedures including primary surgery are performed by experienced surgeons and that prolonged ovarian suppression is established postoperatively (Vercellini *et al.*, 2009).

#### **4.2 Pelvic denervating procedures**

In these conditions, one of the clinical dilemmas regards the indication for and the potential benefit of reoperation. In women wishing for conception, uterine denervation may be performed in addition to repetitive ablation of endometriotic lesion to improve long-term antalgic results. Laparotomy or laparoscopy plus presacral neurectomy has better results than surgery only in regard to: recurrence of dysmenorrhea at 1-year follow-up (17% and 25%, respectively), dysmenorrhea relief at 6 and 12 month follow-up (87% vs 60%, and 86% vs 57%, respectively), severity of dysmenorrhea, dyspareunia, non-menstrual pelvic pain

Abdominopelvic Complications of Endometriosis 69

The term deep infiltrating endometriosis (DIE) is used to describe infiltrative forms of the disease that involve the uterosacral ligaments, rectovaginal septum, bowel, bladder, or ureters, but is histologically defined in arbitrary manner when endometriotic lesions extending more than 5 mm beneath the peritoneal surface (Chapron *et al.*, 2009) suggest, regardless of location (bladder, intestine, ureter, etc.) that endometriosis is only considered to be DIE when the muscularis is involved (Yantiss *et al.,* 2001). This entity is responsible for refractory pelvic pain, of which the intensity is correlated with the depth of infiltration, and

DIE is thought to arise from several possible mechanisms: (i) The Sampson's retrograde menstruation theory: during menstruation, endometrial tissue refluxes trough the fallopian tubes, implanting and growing on the serosal surface of abdominal and pelvic organs, influenced by local hormones and immune, genetic and environmental factors. This results in peritoneal and ovarian endometrial deposits. (ii) The coelomic metaplasia theory proposes that endometriosis develops from metaplasia of the cells that line the pelvic peritoneum. These cells share a common embryological origin with the germinal endometrium of the ovary and the müllerian ducts. Infectious, hormonal or inflammatory stimuli could result in metaplasia of these cells and endometriosis. This theory is supported by the rare occurrence of endometriosis in men and in prepubertal girls. (iii) The embryonic rest theory proposes that metaplasia of müllerian duct remnants in the rectovaginal septum could result in the rectovaginal nodules. (iv) Another theory implies the migration of cells through the lymphatic system or vía hematogenous spread. (v) The neurologic hypothesis is a new concept in the pathogenesis of endometriosis: the lesions seem to infiltrate the large bowel wall along the nerves, at a distance from the primary lesion (Anaf *et al.*, 2004). It is thought that the growth and invasion of endometrial tissue at ectopic sites is due to a process of neovascularizacion mediated by pro-angiogenic factors such as vascular endothelial growth factor (VEGF) (Taylor *et al.*, 2009). Histologically, endometrial nodules are composed of hypertrophic smooth muscle and endometrial glands, similar in

The multifocal distribution of DIE lesions indeed prompted us to cease considering this disease as a single organ pathology but rather, to see it as an "abdomino-pelvic multifocal pathology" (Chapron *et al.*, 2010). The pre-operative work-up (questioning, clinical examination and imaging information) aims to clarify the exact location and likely extension of DIE lesions. This is essential in order to: (i) Specify the surgical procedures required to achieve complete excision of symptomatic DIE lesions, the only way to prevent the recurrence. (ii) Thoroughly describe the surgical risks to the patient. (iii) Obtain the patient's full informed consent, as necessary prior to surgery for a benign pathology responsible for painful symptoms (Chapron *et al.*, 2010). It must take into account that the discovery of a DIE nodule during clinical and/or imaging investigations is not always followed by

Although medical treatment may be effective in some DIE patients, the treatment of choice is surgical excision. The multifocal nature of DIE lesions must be taken into account when defining the surgical strategy (Chapron *et al.*, 2003). Generally, DIE is presented as a pathology with a high risk of recurrence, estimated at around 30%. Often, however, recurrence corresponds to persistence of DIE lesions that were left in place as the result of an

occurs in 30%-40% of the patients with endometriosis (Chapron *et al.*, 2003).

appearance to adenomyosis in the uterus (Brouwer & Woods, 2007).

surgery. Only lesions that give rise to symptoms should be operated on.

incomplete initial surgical removal (Vignali *et al.*, 2005).

**5. Deep infiltrating endometriosis** 

and health-related quality of life at 24-month follow-up (Zullo *et al.*, 2004). However, this technique presents limitations that must be taken into account: first, it is effective in reducing midline pain only, whereas lateral, adnexal pain is not influenced; second, denervation of bowel and bladder cause *de-novo* constipation (15%) and urinary urgency (5%) (Latthe *et al.*, 2007; Zullo *et al.*, 2004); third, great care must be taken to avoid damaging the right ureter and major and midsacral vessels (Berlanda *et al.*, 2010). Systematic performance of presacral neurectomy cannot be recommended, only in patients with central, hipo-gastric pain (Latthe *et al.*, 2007; Vercellini *et al.*, 2009).

The addition of uterosacral ligament resection (i.e., laparoscopic uterosacral nerve ablation) to laparoscopic surgical treatment of endometriosis was not associated with a significant difference in any pain outcomes (Latthe *et al.*, 2007).

#### **4.3 Definitive surgery**

Definitive surgery in women with chronic pain is a controversial procedure, especially in young women. However, this factor should be carefully evaluated in order to offer a reliable prognosis to women affected by an oestrogen-responsive disease (Vercellini *et al.*, 2009). The surgical solution in women with recurrent symptoms after previous conservative procedures for endometriosis should be based on the desire for conception, and the preoperative patient assessment must be complete, including testing for bowel dysmotility, urologic disorders, musculoskeletal lesions, and psycho-socio-environmental factors (Berlanda *et al.*, 2010). The risk of depressive symptoms after definitive procedures must be taken into account, particularly in young patients (Vercellini *et al.*, 2009). The definitive therapy for endometriosis is represented by total hysterectomy, bilateral salpingooophorectomy and removal of all endometriotic lesions, in particular deep lesions involving the pouch of Douglas, the anterior pouch or the ureter. The operation mimic radical hysterectomy (Berlanda *et al.*, 2010).

When pregnancy is no longer an issue and the woman reveals good psychological stability, hysterectomy with or without bilateral salpingo-oophorectomy may be considered and offers the best outcome. The presence of multiple pelvic symptoms, previous use of a GnRH agonist, and absence of pain resolution predict the likelihood of subsecuent hysterectomy (Learman *et al.*, 2007). Few studies address the advantages of hysterectomy for severe pelvic pain associated with endometriosis. Standard extrafascial hysterectomy is associated with increased recurrence of pain than radical hysterectomy with removal of deep endometriotic lesions (31% vs 0%) (Fedele *et al*., 2005a).

The decision to preserve or remove the ovaries should be based on patient's age and intraoperative gonadal conditions. Bilateral oophorectomy substantially reduces the risk of recurrent symptoms and reoperation due to pelvic pain over the ovarian-preserving surgery (10% vs 62%, and 3.7-8% vs 19.2-31%, respectively). Preservation of both ovaries at hysterectomy for symptomatic endometriosis increased the risk of reoperation by 2.4 to 8.1 (Shakiba *et al.*, 2008). Nonetheless, whenever possible at least one gonad should be preserved in young women, especially in those with objections to the use of oestrogenprogestogens (Shakiba *et al.*, 2008). The effect of postoperative medical treatment on the probability of pain relapse should be taken into account after both conservative and definitive procedures.
