**4. Proposed molecular mechanism for implantation failure in endometriosis and future treatment strategies**

In the present study, a hypothesis correlating various factors responsible for implantation failure in endometriosis is proposed (Figure 16). It is well established that endometriosis is an estrogen-dependent disorder. As mentioned earlier, estrogen regulates the expression of MMP-2 and MMP-9 in matrix turnover and VEGF mediated angiogenic activities in various physiological and pathological conditions. Based on our findings, we hypothesize that dysregulation of sex steroids induces over-expression of COX-2 in the endometrium of women with endometriosis. This, in turn, affects endometrial remodelling by up-regulating the expression of MMP-2 and -9, the major molecules responsible for matrix degradation and also increases the expression of VEGF and its receptors, considered to be key angiogenic molecules. This hypothesis is further evidenced by abnormal expression of implantation markers in these women suggesting poor endometrial receptivity and high rate of implantation failure. Molecules which can effectively control excessive endometrial matrix degradation by inhibiting over-expression of various factors responsible for matrix turnover and angiogenesis may be considered as a new therapeutic option for the treatment of endometriosis.

Fig. 16. Schematic representation of the molecular mechanism regulating the process of endometrial receptivity in endometriosis during implantation window

### **5. References**

338 Endometriosis - Basic Concepts and Current Research Trends

Endometrial expression of VEGF and its receptors VEGFR1 and VEGFR2 were observed to be lower and higher respectively in women with endometriosis when compared with controls.

**4. Proposed molecular mechanism for implantation failure in endometriosis** 

In the present study, a hypothesis correlating various factors responsible for implantation failure in endometriosis is proposed (Figure 16). It is well established that endometriosis is an estrogen-dependent disorder. As mentioned earlier, estrogen regulates the expression of MMP-2 and MMP-9 in matrix turnover and VEGF mediated angiogenic activities in various physiological and pathological conditions. Based on our findings, we hypothesize that dysregulation of sex steroids induces over-expression of COX-2 in the endometrium of women with endometriosis. This, in turn, affects endometrial remodelling by up-regulating the expression of MMP-2 and -9, the major molecules responsible for matrix degradation and also increases the expression of VEGF and its receptors, considered to be key angiogenic molecules. This hypothesis is further evidenced by abnormal expression of implantation markers in these women suggesting poor endometrial receptivity and high rate of implantation failure. Molecules which can effectively control excessive endometrial matrix degradation by inhibiting over-expression of various factors responsible for matrix turnover and angiogenesis may be considered as a new therapeutic option for the treatment of

Fig. 16. Schematic representation of the molecular mechanism regulating the process of

endometrial receptivity in endometriosis during implantation window

**and future treatment strategies** 

endometriosis.


Alteration in Endometrial Remodeling: A Cause for Implantation Failure in Endometriosis? 341

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**18** 

Hendi Hendarto

*Indonesia* 

*Dept. of Obstetric & Gynecology Faculty of Medicine, University of Airlangga / Dr. Soetomo Hospital, Surabaya,* 

**Pathomechanism of Infertility in Endometriosis** 

Endometriosis is defined as the presence of endometrial-like tissue outside the uterus, which induces a chronic, inflammatory reaction (Kennedy *et al*., 2005). Infertility is one of clinical manifestation of endometriosis showed by the difference of fecundity. At our tertiary hosital pelvic endometriosis is frequently found in infertile women: 23,8 % (1987), 37,2 % (1993)

An association between endometriosis and infertility has repeatedly been reported in the literature, but an absolute cause-effect relationship has not yet been confirmed. The controversy regarding whether endometriosis is a cause of infertility or an incidental finding is ongoing (ASRM, 2006; Gupta *et al*., 2008). Many theories of endometriosis which may impair fertility have been suggested during the years, and new hypotheses and approaches to the problem have arisen with the application of assisted reproduction techniques (Garrido *et al*., 2002). Data on the impact of endometriosis on the results of in-vitro fertilization and embryo transfer (IVF-ET) treatment are not consistent. Several theories have been proposed to identify the pathomechanism of infertility in endometriosis. None of these theories can completely explain these association. Based on many reports the possible mechanisms that could cause infertility in endometriosis are pelvic adhesion and endometrioma and also excess production of inflammatory factors in micro environment that both play a role in alteration fertility function. Severe endometriosis is associated with pelvic adhesions leading to a possible mechanic or anatomic disturbance of fertility, in the other hand a mild stage may have a direct and indirect negative effect on folliculogenesis, oocyte development, sperm function, embryogenesis, and endometrium receptivity (Barnhart *et al*., 2002). Our aim in the present review is to describe an update on several approaches of the pathomechanism of infertility in endometriosis, based on its impact on a number of pathologic conditions, such as: pelvic adhesion and endometrioma, abnormal folliculogenesis and impaired oocyte function, altered sperm function, reduced embryo

The mechanisms by which endometriosis impairs fertility have not been completely determined but are likely varied. Ovarian involvement and adhesion that block tubal motility and pick-up of the egg could be a main causative of mechanical interference on

and 50 % (2002) cases of diagnostic laparoscopy (Samsulhadi, 2002).

quality, and impaired endometrium receptivity.

**2. Pelvic adhesion and endometrioma** 

**1. Introduction** 

