**5. Endometriosis and its therapies**

As an estrogen-dependent disease, endometriosis treatment has aimed at reducing estrogen concentrations with reversible therapies, using oral contraceptives in a cyclical or continuous fashion as well as with GnRH analogues as first line medical treatments. Progestins, aromatase inhibitors (AIs) and, less frequently, androgens are also used. Removing lesions in a conservative surgery, or even having a radical intervention when the extent of the disease is major, is the surgical approach nowadays available. The most ordinary way of treating endometriosis is attacking from both flanks, with the surgical intervention and dealing with the symptoms with the drug therapy. In any case, the disease is likely to reappear after cessation of therapy; in fact, recurrence rate for endometriosis is between 4-25% (Meuleman et al., 2011).

#### **5.1 PGE2 synthesis inhibition and pain treatment**

122 Endometriosis - Basic Concepts and Current Research Trends

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;

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

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

As an estrogen-dependent disease, endometriosis treatment has aimed at reducing estrogen concentrations with reversible therapies, using oral contraceptives in a cyclical or continuous fashion as well as with GnRH analogues as first line medical treatments. Progestins, aromatase inhibitors (AIs) and, less frequently, androgens are also used. Removing lesions in a conservative surgery, or even having a radical intervention when the extent of the disease is major, is the surgical approach nowadays available. The most ordinary way of treating endometriosis is attacking from both flanks, with the surgical intervention and dealing with the symptoms with the drug therapy. In any case, the disease is likely to reappear after cessation of therapy; in fact, recurrence rate for endometriosis is

endometriosis to control the pain and the development of the pathology.

Lumsden et al., 1983).

inflammation (Smith et al., 2007).

**5. Endometriosis and its therapies** 

between 4-25% (Meuleman et al., 2011).

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

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, the ultimate goal is to lower the concentrations of PGE2.

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

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

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