**4. Prostaglandins and pelvic pain**

Endometriosis has been traditionally included among the most important causes of pelvic pain in women of reproductive age. A recent case-control study described that 73% of women with endometriosis reported experiencing abdominopelvic pain, dysmenorrhea, or menorrhagia compared with only a 20% of the controls (Ballard et al., 2008).

The role of PGs has been examined in women suffering from heavy menstrual bleeding and dysmenorrhea (Maybin et al., 2011). Dysmenorrhea is defined as the excessive pain during menstruation; and menorraghia or heavy menstrual bleeding is the excessive menstrual blood loss during the menstrual periods. These may be primary disorders or secondary to endometrial pathology such as endometriosis (Maybin et al., 2011; Tietjen et al., 2006).

Involvement of Prostaglandins in the Pathophysiology of Endometriosis 123

One of the most inhabilitating symptoms of endometriosis for carrying a normal life is the elevated pelvic pain patients experience. It includes pain before and during periods, during sexual intercourse, while urinating or defecating and during menstruation. It has been of great importance to provide the patient with a better quality of life ameliorating pain symptoms. Elevated concentrations of PGE2 in peritoneal fluid from endometriosis patients is the major

There have been done a large number of studies focusing on the inhibition of COXs activity. Whether it is blocking simultaneously COX-1 and COX-2 or with selective COX-2 inhibitors,

NSAIDs, among them: ibuprofen, naproxen, diclofenac or aspirin; are used primarily for pain treatment, from a headache to menstrual cramps, from a backache to treating an inflammation due to a sprain. These NSAIDs are non-selective COX inhibitors; this means that they prevent the synthesis of PGs from both COXs. Of course, as a constitutively and ubiquitously expressed enzyme, COX-1 inhibition has side effects that should be avoided. Gastrointestinal ulcer is not a rare effect after long term inhibition of COX-1 (Wadman,

Celecoxib belongs to the family of NSAIDs with high selectivity for COX-2 inhibition. Other coxibs have been developed too (rofecoxib, valdecoxib) but were withdrawn from the market in the mid 2000s by the Federal Drug and Food Administration (FDA) of the United States of America because they were proven to have serious cardiovascular adverse events. Coxibs were and are mostly used in arthritis; the one still available for purchase, celecoxib, is prescribed in familial adenomatous polyposis and as an adjuvant in breast cancer (Basu et al., 2006; Falandry et al., 2009; Iwama, 2009; Jankowski & Hunt, 2008; Lynch et al., 2010). Celecoxib has not been approved yet for the treatment of endometriosis. There is one study that evaluated the effectiveness of a COX-2 specific inhibitor on relieving pain symptoms associated to endometriosis after a conservative surgery. Cobellis and coworkers demonstrated in their study that rofecoxib was effective for the management of pain and no

Ferrero and coworkers, recently published a review where they compilated information on the use of AIs and how they contributed to diminish endometriosis related pain. This systematic study shows that the AIs, letrozole and anastrozole, are effective in treating pain symptoms; when withdrawn symptoms reappear, but they cannot be used for a long term therapy because of the adverse effects these compounds have on bone density (Ferrero et al., 2011). Endometriosis patients need chronic treatment, and this could be achieved combining

cause thought to be involved in pain and inflammation processes (Wu et al., 2002).

**5.1 PGE2 synthesis inhibition and pain treatment** 

the ultimate goal is to lower the concentrations of PGE2.

2007); this is why COX-2 selective inhibitors have been developed.

recurrence occurred during the six months of treatment (Cobellis et al., 2004).

AIs with a hormonal therapy to reduce the loss of bone density (Ferrero et al., 2011).

**5.2 PGE2 synthesis inhibition and the control over endometriosis development** 

There have been conducted several studies in which AIs were used and the progression of endometriosis was evaluated. When letrozole or anastrozole were added to endometrial epithelial cells from endometriosis patients in culture, cell proliferation was inhibited and apoptosis augmented (Meresman et al., 2005). When the same two compounds were used for the treatment of surgically induced endometriosis in mice, not only cell proliferation was diminished and apoptosis increased within the endometriotic like lesion, but PGE was also

The pelvic pain of dysmenorrhea has been demonstrated to be mediated through the action of PGE2 and a direct relationship between the severity of dysmenorrhea and the production of PGs has been observed in endometriosis (Coco, 1999; Koike et al., 1992; Nasir & Bope, 2004). As well, analysis of menstrual fluid from women suffering from dysmenorrhea revealed augmented levels of PGE2 and PGF2α (Dawood & Khan-Dawood, 2007a, 2007b; Lumsden et al., 1983).

Increased synthesis of PGE2 and PGF2α in the endometrium has important implications for menstruation (Baird et al., 1996). PGE2 is a potent vasodilator leading to increased oedema and contributing to pain at time of menstruation. Increased COX-2 and enhanced PGE2–EPinduced cAMP production has been found by Smith and coworkers in the endometrium of women with objective heavy menstrual bleeding. These authors suggest that the increased expression of the rate-limiting COX enzymes in the endometrium of women with heavy menstrual blood loss will lead to an increase in PG production and to a magnified inflammation (Smith et al., 2007).

In addition, there is well reported evidence for the hyperalgesic properties of PGs; and EP receptors have been shown elevated in sensory neurons that lead to increased pain perception (Bley et al., 1998; Levine & Taiwo, 1990). Wienecke and coworkers also demonstrated that PGE2 induces headache in healthy subjects by sensitization of cranial perivascular sensory afferents (Wienecke et al., 2009). Therefore, PG inhibition usually resolves the pain and many studies have demonstrated the efficacy of NSAIDs and specific COX-2 inhibitors in relieving dysmenorrheic pain (Coco, 1999; Hayes & Rock, 2002). Suprofen, ibuprofen and acetaminophen were shown to be efficient not only for pain relief but for menstrual fluid PGs suppression as well (Dawood & Khan-Dawood, 2007a, 2007b).

A recent study suggests that the major modality to substantially alleviate pain in endometriosis is suppression of ovarian function and induction of a steady hormonal condition, anovulation and, eventually, amenorrhea (Vercellini et al., 2011). Hormonal manipulation and surgery have been found to be efficient in the management of pelvic pain associated to endometriosis (Vercellini et al., 2011). Oral contraceptives, GnRH agonists, danazol and progestins have been shown to reduce the production of PGs, which are responsible in large part for pelvic pain (Crosignani et al., 2006; Venturini et al., 1997).

Given that, further investigations should focus on how to inhibit the production of PGs in endometriosis to control the pain and the development of the pathology.
