**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

Involvement of Prostaglandins in the Pathophysiology of Endometriosis 125

overexpressed in several pathological circumstances as different types of cancers and other

There is no doubt that PGE2 is implicated in the aetiopathogenesis of endometriosis and contributes to the development and maintenance of the disease. The elevated levels of PGs found in the peritoneal fluid from patients with endometriosis are mainly produced by peritoneal macrophages and endometriotic tissues. As well, the peritoneal estrogens, proinflammatory and pro-angiogenic molecules contribute to elevate the expression of COX-2 and consequently the levels of PGE2 in endometriosis patients. The pelvic pain associated to endometriosis has also been demonstrated to be mediated through the action of PGE2 and

Given these data, further investigations should focus on how to inhibit the production of

Attar, E., Tokunaga, H., Imir, G., Yilmaz, M.B., Redwine, D., Putman, M., Gurates, B., Attar,

Baird, D.T., Cameron, S.T., Critchley, H.O., Drudy, T.A., Howe, A., Jones, R.L., Lea, R.G., &

Ballard, K.D., Seaman, H.E., de Vries, C.S., & Wright, J.T. Can symptomatology help in the

Banu, S.K., Lee, J., Speights, V.O., Jr., Starzinski-Powitz, A., & Arosh, J.A. Cyclooxygenase-2

Basu, G.D., Pathangey, L.B., Tinder, T.L., Gendler, S.J., & Mukherjee, P. Mechanisms

Basu, G.D., Tinder, T.L., Bradley, J.M., Tu, T., Hattrup, C.L., Pockaj, B.A., & Mukherjee, P.

Bilotas, M., Meresman, G., Stella, I., Sueldo, C., & Baranao, R.I. Effect of aromatase inhibitors

R., Yaegashi, N., Hales, D.B., & Bulun, S.E. Prostaglandin E2 via steroidogenic factor-1 coordinately regulates transcription of steroidogenic genes necessary for estrogen synthesis in endometriosis. *Journal of Clinical Endocrinology and Metabolism*,

Kelly, R.W. Prostaglandins and menstruation. *European Journal of Obstetrics & Gynecology and Reproductive Biology.*, Vol.70, No.1, (December 1996), pp. (15-17),

diagnosis of endometriosis? Findings from a national case-control study--Part 1. *BJOG: An International Journal of Obstetrics and Gynaecology*, Vol.115, No.11, (October

regulates survival, migration, and invasion of human endometriotic cells through multiple mechanisms. *Endocrinology*, Vol.149, No.3, (March 2008), pp. (1180-1189),

underlying the growth inhibitory effects of the cyclo-oxygenase-2 inhibitor celecoxib in human breast cancer cells. *Breast Cancer Research*, Vol.7, No.4, (April

Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO. *Journal of Immunology*, Vol.177, No.4, (August 2006), pp. (2391-2402), 0022-1767

on ectopic endometrial growth and peritoneal environment in a mouse model of

PGs in endometriosis, to control the pain and the development of the pathology.

We thank Dr. Gustavo Leirós for providing technical assistance in designing figures.

Vol.94, No.2, (February 2009), pp. (623-631), 0021-972X

inflammation related diseases.

**7. Acknowledgement** 

0301-2115

0013-7227

2008), pp. (1382-1391), 1470-032

2005), pp. (R422-R435), 1465-5411

**8. References** 

inhibition of PG production usually resolves the pain.

decreased in the peritoneal fluid of mice treated with letrozole but not with anastrozole (Bilotas et al., 2010).

Much research has been done evaluating the effects of inhibiting COXs activity regarding the development of endometriosis with *in vivo* and *in vitro* approaches. Celecoxib has been shown to have anti-proliferative and pro-apoptotic effects over endometrial epithelial cells in culture obtained from biopsies of women with and without endometriosis; it was also effective in diminishing COX-2 expression, reducing the synthesis of VEGF and PGE2 (Olivares et al., 2008). Similar results had previously been achieved in various cancer models (Basu et al., 2005; Chun & Surh, 2004). Given that the endometrial cells at the ectopic site have a very similar behaviour to neoplasic cells; it is not surprising that treatments aim at the same targets.

There is one very complete work from Efstathiou and coworkers where they compared seven different selective (rofecoxib and celecoxib) and non-selective (aspirin, ibuprofen, indomethacin, naproxen and sulindac) NSAIDs on the establishment and development of endometriosis in a mouse model (Efstathiou et al., 2005). In this work, celecoxib given orally twice daily and indomethacin administered subcutaneously daily for four weeks, were both effective in significantly diminishing the percentage of established lesions compared to the control group. All the NSAIDs evaluated in the same study, except for aspirin, significantly inhibited the growth of the established lesions compared to the control group (Efstathiou et al., 2005). A study in a rat model of endometriosis, evaluated the effect of parecoxib, another selective COX-2 inhibitor, and showed not only a significant reduction in lesion size, but also, a significant inhibition on the expression of VEGF, its receptor Flk-1 and COX-2 compared to the untreated group with endometriosis (Machado et al., 2010). Machado and coworkers also observed a significant reduction of the levels of PGE2 in endometriotic homogeneized tissue treated with parecoxib compared to the untreated group (Machado et al., 2010).

More recently a new approach targeting more than one molecule to prevent the development of the disease has gained importance. Promising results were achieved firstly in cancer models, which targeted COX-2 and PPARγ. This combinational therapy resulted in the inhibition of cell proliferation and apoptosis enhancement *in vitro* and increased overall survival rate *in vivo* (Mustafa & Kruger, 2008; Sun et al., 2009). When celecoxib was combined with rosiglitazone, a PPARγ agonist, for the treatment of surgically induced endometriosis in a mouse model, a reduced number of established lesions was observed as well as the volume of established ones; also induction of apoptosis and reduction of the cell proliferation rate and vascularization was achieved (Olivares et al., 2011).

Reducing PGE2 concentration in the peritoneal environment would not only be relieving the pain caused by the disease but would also be affecting its development. This is one of the main goals of endometriosis treatments; now it is time to decide whether the drugs used to achieve these results are the appropriate ones to manage with this disease.
